Idazoxan and Response to Typical Neuroleptics in Treatment-Resistant Schizophrenia

Litman, Robert E.; Su, Tung Ping; Potter, William Z.; Hong, Walter W.; Pickar, David

doi:10.1192/bjp.168.5.571

Cited by 121 publications

(67 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…104 Indeed, combined treatment of a selective a 2 adrenergic receptor antagonist with a typical antipsychotic drug has been reported to produce a profile of antipsychotic activity similar to clozapine. 105 Thus, balancing a 2 adrenergic receptor activity to achieve both antipsychotic and pro-cognitive efficacy may be challenging.…”

Section: Serotonin 5-ht 4 Receptorsmentioning

confidence: 99%

The pipeline and future of drug development in schizophrenia

2007

View full text Add to dashboard Cite

While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.

show abstract

Section: Serotonin 5-ht 4 Receptorsmentioning

confidence: 99%

The pipeline and future of drug development in schizophrenia

2007

View full text Add to dashboard Cite

show abstract

“…Clozapine displays nanomolar affinity for the ␣ 2C adrenoceptor (K I 9.1 nM) and some se-lectivity relative to the ␣ 2A subtype (K I 50 nM) (Schotte et al 1996). It has been speculated that clozapine's superior therapeutic activity is at least partly explained by ␣ 2 -adrenoceptor blockade (Nutt 1994;Litman et al 1996;Hertel et al 1999). Other therapeutic effects of clozapine may also be related to ␣ 2 -adrenoceptor blockade.…”

Section: Affinity For ␣ 2a and ␣ 2c Adrenoceptorsmentioning

confidence: 99%

“…The elucidation of the multiple receptor interactions of clozapine suggested that other neurotransmitter systems may also play a role in the efficacy and tolerability of that molecule. Particularly, the antiadrenergic effects of clozapine are now receiving increased attention (Nutt 1994;Litman et al 1996;Hertel et al 1999). Iloperidone is a new psychotropic agent currently undergoing Phase III trials for the treatment of psychotic disorders (Figure 1).…”

mentioning

confidence: 99%

Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

Kalkman

Subramanian

Hoyer

2001

Neuropsychopharmacology

View full text Add to dashboard Cite

Iloperidone is a novel psychotropic compound currently undergoing Phase III trials. Its affinity for human dopamine and 5-HT receptors has been reported previously (Kongsamut et al. 1996). This report presents the affinity of iloperidone for a largely extended number of human neurotransmitter receptors. In a few instances human receptors were not available and receptor studies were performed on tissues from laboratory animals. The present data, supplemented with those of Kongsamut et al. (1996) The prototypical classical neuroleptic agent haloperidol is an effective antipsychotic compound (Leucht et al. 1999) which, unfortunately, also induces severe extrapyramidal side effects (EPS) and hyperprolactinemia. The term "atypical antipsychotic" was originally introduced to describe compounds, such as clozapine, which not only suppressed psychotic symptoms, but differed from haloperidol by having a low tendency to induce EPS and increase plasma prolactin levels. It is postulated that dopamine D 2 receptor blockade is the mechanism by which antipsychotic activity is achieved (Creese et al. 1976;Seeman et al. 1976 Conley et al. 1999;Taylor and Duncan-McConnell 2000). The elucidation of the multiple receptor interactions of clozapine suggested that other neurotransmitter systems may also play a role in the efficacy and tolerability of that molecule. Particularly, the antiadrenergic effects of clozapine are now receiving increased attention (Nutt 1994;Litman et al. 1996;Hertel et al. 1999). Iloperidone is a new psychotropic agent currently undergoing Phase III trials for the treatment of psychotic disorders (Figure 1). Iloperidone was selected from a large series of piperidinyl-benzisoxazoles because it showed a 300-fold greater potency in a test for limbic activity (inhibition of apomorphine-induced climbing) than in a test for nigrostriatal activity (inhibition of apomorphine-induced stereotypy) . The large difference of potency of iloperidone in these tests is expected to result in an improved ratio of therapeutic effect to EPS liability compared with standard antipsychotics. Previous studies have investigated the receptor binding profile of iloperidone with rat receptors ) and a limited number of human homologues of dopamine and 5-HT receptor subtypes (Kongsamut et al. 1996). These experiments demonstated that iloperidone displays the desired 5-HT 2A /D 2 affinity ratio. The aim of the present study was to determine the receptor affinity profile of iloperidone at a wider range of human neurotransmitter receptors. In resemblance to clozapine, it was noted that iloperidone possesses high affinity for norepinephrine ␣ 1 -and ␣ 2C adrenergic receptors. METHODSThe radioligand receptor binding assays are listed in Table 1. MaterialsRadioligands were purchased from NEN Life Science Products, USA, except for 3 H-RX821002 and 3 H-Mesulergine, which were obtained from Amersham Pharmacia Biotech Ltd, UK, and 125 I-GTI which was obtained from ANAWA, Switzerland. Iloperidone was synthesized by Hoechst Marion Roussel. Unless speci...

show abstract

“…In some (Breier et al 1994b;Schulz et al 1997;Fleischhaker et al 1998), but not all (Brown et al 1997) studies, plasma NE increases have been related to clinical improvement, suggesting that this pharmacological effect may play a role in clozapine's beneficial central actions. In this context, findings implicating noradrenergic dysregulation in the pathophysiology of schizophrenia (Stein and Wise 1971;Sternberg 1984;Breier et al 1990;Rao and Moller 1994;Breier 1994;Yamamoto et al 1994;Litman et al 1996;Breier et al 1998;Goff and Evins 1998;Friedman et al 1999a;Friedman et al 1999b;Klimek et al 1999) further support inquiry into the relevance of noradrenergic mechanisms in the action of APDs.We have reported previous data suggesting that high plasma NE levels in clozapine-treated patients result from increases in the appearance rate of the endogenously released NE in the plasma (spillover) rather than from decreased neuronal uptake of NE, inhibition of intraneuronal monoamine oxidase (MAO), or adrenoceptor antagonism . Risperidone, the next atypical antipsychotic drug marketed in the United States after clozapine, is associated with a low incidence of EPS and may have improved efficacy compared with conventional agents (Kane and McGlashan 1995;Pickar 1995;Campbell et al 1999).…”

mentioning

confidence: 96%

mentioning

confidence: 96%

Effects of Risperidone on the Peripheral Noradrenegic System in Patients with Schizophrenia A Comparison with Clozapine and Placebo

Elman

Goldstein

Green

et al. 2002

Neuropsychopharmacology

View full text Add to dashboard Cite

Risperidone is an atypical antipsychotic drug that increases plasma norepinephrine (NE) levels, but the mechanism behind this effect is unclear. We measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE ( 3 H-NE) in risperidone-Clozapine is an atypical antipsychotic drug (APD) with efficacy superior to that of conventional agents and with little or no extrapyramidal signs or symptoms (EPS) (Kane et al. 1988;Lieberman et al. 1989;Breier et al. 1994a;Meltzer 1995;Meltzer et al. 1996). Because these advantageous therapeutic properties are accompanied by unusually severe side effects, scientists have been searching for clozapine-like APDs that would share its beneficial features but not induce bone marrow toxicity, seizures, or hypotension. This search has resulted in the introduction of four "newer atypical APDs" (i.e., risperidone, olanzapine, quetiapine, and ziprasidone), all of which have important effects on both dopaminergic and serotonergic neurotransmitter systems. Because none of these compounds has been proven as efficacious as the prototype, clozapine, in the treatment of resistant cases, continued research is focusing on other neurotransmitter systems affected by clozapine.Clozapine profoundly increases norepinephrine (NE) levels in both CSF (Ackenheil 1989;Lieberman et al. 1989;Lieberman et al. 1991;Pickar et al. 1992) and plasma (Pickar et al. 1992;Green et al. 1993;Davidson et al. 1993;Breier 1994;Breier et al. 1994b;Schulz et al. 1996;Schulz et al. 1997;Brown et al. 1997;Fleischhaker et al. 1998;Elman et al. 1999), an effect not seen with typical APDs. In some (Breier et al. 1994b;Schulz et al. 1997;Fleischhaker et al. 1998), but not all (Brown et al. 1997) studies, plasma NE increases have been related to clinical improvement, suggesting that this pharmacological effect may play a role in clozapine's beneficial central actions. In this context, findings implicating noradrenergic dysregulation in the pathophysiology of schizophrenia (Stein and Wise 1971;Sternberg 1984;Breier et al. 1990;Rao and Moller 1994;Breier 1994;Yamamoto et al. 1994;Litman et al. 1996;Breier et al. 1998;Goff and Evins 1998;Friedman et al. 1999a;Friedman et al. 1999b;Klimek et al. 1999) further support inquiry into the relevance of noradrenergic mechanisms in the action of APDs.We have reported previous data suggesting that high plasma NE levels in clozapine-treated patients result from increases in the appearance rate of the endogenously released NE in the plasma (spillover) rather than from decreased neuronal uptake of NE, inhibition of intraneuronal monoamine oxidase (MAO), or adrenoceptor antagonism . Risperidone, the next atypical antipsychotic drug marketed in the United States after clozapine, is associated with a low incidence of EPS and may have improved efficacy compared with conventional agents (Kane and McGlashan 1995;Pickar 1995;Campbell et al. 1999). Interestingly, risperidone has also recently been observed in a clinical study to produce a modest (i.e., 58%) inc...

show abstract

Idazoxan and Response to Typical Neuroleptics in Treatment-Resistant Schizophrenia

Abstract: The antagonism of alpha 2 receptors augmented therapeutic response to typical neuroleptic treatment in treatment-resistant patients with schizophrenia. This antagonism may contribute to clozapine's superior antipsychotic effects.

Cited by 121 publications

References 18 publications

The pipeline and future of drug development in schizophrenia

The pipeline and future of drug development in schizophrenia

Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

Effects of Risperidone on the Peripheral Noradrenegic System in Patients with Schizophrenia A Comparison with Clozapine and Placebo

Contact Info

Product

Resources

About