Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile

Schmidt, Anne W.; Lebel, Lorraine A.; Howard, Harry; Zorn, Stevin H.

doi:10.1016/s0014-2999(01)01188-8

Cited by 257 publications

(143 citation statements)

References 9 publications

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“…Although the clinical effects of ziprasidone were evident after 28 days of treatment, and ziprasidone has the highest potency among atypical antipsychotics to block 5-HTT, our data did not confirm the hypothesis that ziprasidone treatment decreases platelet 5-HT concentration, at least not in the doses used in our study. Ziprasidone is an atypical antipsychotic, with higher ratio of 5-HT2A/D2, 5-HT2C/D2 and 5-HT1A/D2 receptor binding than other antipsychotic drugs (Schmidt et al 2001;Stahl and Shayegan 2007). It also blocks the serotonin transporter (5-HTT) and inhibits synaptic 5-HT reuptake (Tatsumi et al 1999).…”

Section: Discussionmentioning

confidence: 99%

The lack of effect of ziprasidone on platelet serotonin concentration in schizophrenic patients

et al. 2011

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and inhibits synaptic 5-HT reuptake. These effects might be responsible for the antidepressant effect of ziprasidone.Objectives Since there is a lack of in vivo data on the effects of ziprasidone on 5-HT concentration in humans, the aim of the study was to investigate the effect of ziprasidone 2 treatment on platelet 5-HT concentration in patients with schizophrenia or schizoaffective disorders.Methods In and open-label study, the effect of ziprasidone (average dose of 109 mg/day) on platelet 5-HT concentration (determined fluorimetrically) was evaluated at baseline and after 7 and 28 days of treatment in 21 male and female patients with schizophrenia or schizoaffective disorders.Results Ziprasidone treatment for 7 or 28 days did not significantly change baseline platelet 5-HT concentration in male and female schizophrenic patients. Platelet 5-HT concentration was not correlated with gender, age and smoking status of patients. ConclusionsThere was a lack of effect of ziprasidone treatment on platelet 5-HT concentration in male and female schizophrenic patients. Although the clinical effects of ziprasidone were evident after 28 days of treatment, and ziprasidone has the highest potency among atypical antipsychotics to block 5-HTT, our data did not confirm the hypothesis that ziprasidone treatment decreases platelet 5-HT concentration, at least not in the doses used in our study.

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Section: Discussionmentioning

confidence: 99%

The lack of effect of ziprasidone on platelet serotonin concentration in schizophrenic patients

et al. 2011

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“…5 Although rapid dissociation from the D 2 receptor in vitro is a good predictor of low EPS potential in patients, this "hit-and-run" action may not be acceptable as a general mechanism of atypicality because it does not account for the fact that the atypical antipsychotics olanzapine, risperidone, and ziprasidone all have high D 2 affinities and slow dissociation rates from the receptor. 6,7 Another D 2 -centered mechanism that has gained currency is dopamine D 2 partial agonism. In the spectrum of pharmacological actions that range from agonism to inverse agonism, the actions of dopamine partial agonists (DPAs) on D 2 receptors lie somewhere between full agonism and silent antagonism (FIG.…”

Section: Figmentioning

confidence: 99%

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Kim¹,

Maneen²,

Stahl

2009

Neurotherapeutics

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Summary: Attempts to develop selective ("magic bullet") drugs for the treatment of schizophrenia have been frustrated by the complex etiology of the disease. The symptomatology of schizophrenia does not appear to arise from a single neurobiological entity, but rather may be derived from pathology at one or more receptor types. This has prompted multifactorial approaches to the development of new therapeutics, as embodied by polypharmacy and an alternative (or augmentative) strategy known as "intramolecular polypharmacy," in which a single drug possesses the capacity to affect multiple receptor types.Atypical antipsychotics are a well-known example of this approach; each atypical possesses a unique portfolio of activities at receptors that may contribute to therapeutic effects (as well as side effects). In this article we present a discussion of some of the receptor targets that are currently thought to mediate symptoms of schizophrenia, as well as their possible implications for the design of future multifunctional antipsychotics.

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“…and 5-HT 1B/1D (K i ¼ 2.0 nM) receptors as an antagonist, and for the 5-HT 1A receptor (K i ¼ 2.5 nM) as an agonist (Schmidt et al, 2001;Seeger et al, 1995). It has moderate affinity for the a 1 and H 1 receptors.…”

Section: Introductionmentioning

confidence: 99%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

Neuropsychopharmacol

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Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.

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Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile

Cited by 257 publications

References 9 publications

The lack of effect of ziprasidone on platelet serotonin concentration in schizophrenic patients

The lack of effect of ziprasidone on platelet serotonin concentration in schizophrenic patients

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Occupancy of Agonist Drugs at the 5-HT1A Receptor

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