Das klinische Wirkungsbild von Clozapin: (Untersuchung mit dem AMP-System)

Angst, J.; Bente, D; Berner, P.; Heimann, H; Helmchen, Hanfried; Hippius, H

doi:10.1055/s-0028-1094313

Cited by 125 publications

(17 citation statements)

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“…At doses of 200 to 900 mg/day, clozapine was found to produce antipsychotic action with minimal EPSs or prolactin elevation in patients with schizophrenia, an atypical profile compared with other APDs (52,53). Comparison of the affinities of typical and atypical APDs for DA D 1 and D 2 and 5-HT 2A receptors led to the hypothesis that one type of atypical APD could be identified by a higher affinity for 5-HT 2A receptors than for D 2 receptors (54).…”

Section: Treating Parkinson's Disease Psychosis: From Clozapine To Pimentioning

confidence: 99%

Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

Meltzer¹,

Roth²

2013

J. Clin. Invest.

103

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Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT 2C and 5HT 2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively. Serotonin receptors and signal transductionSerotonin, which was known to be the principal vasoconstricting substance found in serum, was chemically identified as 5-hydroxytryptamine by Rapport and colleagues in 1948 (1). Although the effects of serotonin on smooth muscle and other peripheral organs were long appreciated, it wasn't until its structural similarity to lysergic acid diethylamide (LSD) was noted that serotonin and its receptors were linked to neurotransmission (2). Distinct serotonin receptor subtypes were proposed in 1957 (3), with the 5-HT1 receptors having high affinity for serotonin and the 5-HT2 receptors having relatively low affinity for 5-HT. The so-called 5-HT1 and 5-HT2 receptors identified pharmacologically by Gaddum and colleagues (3) roughly correspond to what are now known as the 5-HT 1 and 5-HT 2 families of receptors ( Figure 1).With the development of radioligand-binding technology, multiple distinct serotonin receptors were identified based principally on their differential radioligand-binding properties. Following the cloning of the β-adrenergic receptor (4), 5-HT 1A (5), the first socalled orphan GPCR, was cloned by Brian Kobilka in collaboration with Marc Caron and others (6, 7). In rapid succession, the large family of G protein-coupled serotonin receptors we now appreciate were identified by molecular cloning technology and characterized by pharmacological and biochemical studies (8, 9), including 5-HT 1B/1D (10) and 5-HT 1E (11), as well as 5-HT 2A (12, 13) and 5-HT 2C (14, 15), which have lower affinities for 5-HT than the other serotonin receptors. The 5-HT 4 receptor was also one of the early 5-HT receptor subtypes identified mainly by radioligand binding and pharmacological studies (refs. 16, 17, and see Figure 1).In terms of signal transduction and pharmacology, we now know that all members of the 5-HT 1 family are intronless and couple to the Gi family of heterotrimeric G proteins -in keeping with the original description of the 5-HT 1A receptor (7). The 5-HT 1 family of receptors has been successfully exploited for the treatment of anxiety and depression with the development of drugs like buspirone (Tabl...

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Section: Treating Parkinson's Disease Psychosis: From Clozapine To Pimentioning

confidence: 99%

Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

Meltzer¹,

Roth²

2013

J. Clin. Invest.

103

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“…A second important advance in the treatment of the negative symptoms has come from the use of clozapine, initially introduced as an antipsychotic agent with a very low incidence of extrapyramidal side effects (Angst et al, 1971). Clozapine was reported to be superior to chlorpromazine in treating the negative symptoms of schizophrenia (Fischer-Cornelssen & Ferner, 1976;Claghorn et al, 1987;Kane et al, 1988;1990) and is becoming a most significant therapy for treatment-resistant schizophrenia (Carpenter & Conley, 1991).…”

Section: Introductionmentioning

confidence: 99%

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Costall

Naylor

1995

British J Pharmacology

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1 The ability of 5-hydroxytryptophan, 5-HT2 receptor antagonists and typical and atypical neuroleptic agents to modify behavioural responding to aversive situations was investigated in the mouse light/dark test and rat social interaction. 2 The administration of 5-hydroxytryptophan inhibited rat social interaction and the exploratory behaviour of mice in the light/dark test.3 The 5-HT2 receptor antagonists, ketanserin, ritanserin, MDL11939, methysergide and RP62203, the neuroleptic agents, spiperone, haloperidol and benperidol, and the atypical neuroleptic agent, clozapine, when administered alone failed to modify mouse or rat behaviour. In contrast, when administered alone, sulpiride in rats and mice and thioridazine in rats disinhibited behaviour. 4 Methysergide, RP62203, ketanserin, ritanserin and MDL11939 antagonized the inhibitory effects of 5-hydroxytryptophan or reversed the inhibitory effects to one of disinhibition. 5 Low doses of spiperone (but not haloperidol or benperidol) also antagonized the inhibitory effects of 5-hydroxytryptophan in the rat but not the mouse. Higher doses of the three neuroleptic agents caused locomotor depression in both rats and mice which obscured any specific changes in behavioural responding to the aversive situations. 6 The disinhibitory profile of sulpiride in both mice and rats and thioridazine in rats was evident during their interaction with 5-hydroxytryptophan. Thioridazine in the mouse and clozapine in rats and mice also reversed the inhibitory effects of 5-hydroxytryptophan to one of disinhibition. 7 In summary, we present evidence that the atypical neuroleptic agents, thioridazine and clozapine, with their known affinity for the 5-HT2 receptors, can mimic the actions of reference 5-HT2 receptor antagonists to antagonize the inhibitory effects of 5-hydroxytryptophan in rodent models of anxiety. The results are intepreted in terms of drug action on different 5-HT2 and other 5-HT receptor subtypes. In addition, thioridazine and sulpiride have disinhibitory effects in their own right which remain to be explained.

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“…Clozapine has been called an 'atypical' neuroleptic because it produces few extrapyramidal side effects and does not appear to cause tardive dyskinesia (Berzewski et al, 1969;Angst et al, 1971;Honigfeld et al, 1984;Meltzer, 1989;Farde et al, 1989). Other properties that distinguish CLZ from typical neuroleptics such as haloperidol (Hal) is the failure to produce long-lasting elevation of plasma prolactin levels, failure to induce dopamine D2 receptor supersensitivity in the striatum after chronic treatment, and inability to inhibit markedly apomorphineinduced circling behaviours in rats with unilateral lesions of their substantia nigra (Coward et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Dopamine release and metabolism in the rat frontal cortex, nucleus accumbens, and striatum: a comparison of acute clozapine and haloperidol

Karoum¹,

Egan²

1992

British J Pharmacology

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1 The effects of the typical and typical neuroleptic agents clozapine (CLZ) (2.5-20mgkg 1, i.p.) and haloperidol (Hal) (0.05-1.Omgkg-1), were compared on dopamine release and metabolism in the rat prefrontal cortex (PFC), nucleus accumbens (ACC) and striatum (ST). Dopamine release was estimated by measuring the steady-state concentration of 3-methoxytyramine (3-MT) and the level of 3-MT 10min after pargyline (3-MT accumulation); dopamine metabolism was evaluated from the steady-state concentrations of its acidic metabolites. 2 Both drugs increased 3-MT accumulation in the PFC in a dose-dependent manner. In contrast to Hal, CLZ failed to increase 3-MT accumulation in the ACC or ST. The ST was the region most sensitive to Hal in terms of 3-MT accumulation and, by inference, dopamine release. 3 Both CLZ and Hal dose-dependently elevated the concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in all 3 brain regions studied. The ACC appears to be the region most sensitive to these drugs in terms of changes in the levels of HVA. 4 The result of the present investigations suggest measurements of 3-MT production in the 3 brain regions analysed might be a useful and simple pharmacological tool in the search for atypical neuroleptic drugs with a selectivity of action for the cortical systems.

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Das klinische Wirkungsbild von Clozapin: (Untersuchung mit dem AMP-System)

Cited by 125 publications

References 1 publication

Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Dopamine release and metabolism in the rat frontal cortex, nucleus accumbens, and striatum: a comparison of acute clozapine and haloperidol

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