Efficacy and Safety of Aripiprazole and Haloperidol Versus Placebo in Patients With Schizophrenia and Schizoaffective Disorder

Kane, John M.; Carson, William H.; Saha, A.; McQuade, Robert D.; Ингенито, Г.; Zimbroff, Dan L.; Ali, Mirza

doi:10.4088/jcp.v63n0903

Cited by 538 publications

(319 citation statements)

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“…In a large, randomized, placebocontrolled study, both doses of AL evaluated (441 mg and 882 mg) administered every 4 weeks over the course of 12 weeks demonstrated robust efficacy compared with placebo (Meltzer et al, 2015). Results of that study are consistent with earlier studies of oral aripiprazole, which also showed efficacy for the acute treatment of schizophrenia at oral doses ranging from 10 to 30 mg per day (Potkin et al, 2003;Kane et al, 2002).…”

Section: Introductionsupporting

confidence: 78%

Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation

Potkin

Risinger

et al. 2017

Schizophrenia Research

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Aripiprazole lauroxil (AL), a new long-acting injectable antipsychotic, demonstrated safety and efficacy in treating acute exacerbation symptoms of schizophrenia in a 12-week placebo-controlled trial of two doses of AL (441 mg and 882 mg) administered every 4 weeks. We performed a post hoc analysis of this trial to evaluate the efficacy of AL in the subgroup of patients with severe psychotic symptoms, defined as those with baseline Positive and Negative Syndrome Scale (PANSS) Total score above the median score of 92 (n = 309). Change from baseline to Day 85 in PANSS Total score; Positive, Negative, and General Psychopathology subscale scores; and overall response rate were assessed. Statistically significant and clinically meaningful improvements in PANSS Total score were demonstrated with AL 441 mg and AL 882 mg, with placebo-adjusted differences of −14.7 (p b 0.0001) and −16.6 (p b 0.0001), respectively. Significant and clinically meaningful findings with both doses of AL were also demonstrated for the PANSS subscales and responder rates. Overall responder rates at Day 85 were significantly greater for AL 441 mg (49%; p b 0.001) and 882 mg (61%; p b 0.001) groups vs. placebo (18%). Common adverse events (N 5%) were schizophrenia, akathisia, headache, insomnia, and anxiety. AL demonstrated robust efficacy in treatment of the subgroup of patients experiencing severe psychotic symptoms. Both doses (441 mg and 882 mg) were effective, with numerically greater improvement in symptoms and proportion of responders favoring the higher dose arm. Both doses had a side effect profile consistent with the known safety profile of aripiprazole.

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Section: Introductionsupporting

confidence: 78%

Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation

Potkin

Risinger

et al. 2017

Schizophrenia Research

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“…In vivo occupancy and functional effects of aripiprazole S Natesan et al idol and risperidone are clinically active from B60% D 2 RO, aripiprazole is effective only at doses 485% D 2 RO (Farde et al, 1992;Kapur et al, 1995;Kapur et al, 1996;Kane et al, 2002;Yokoi et al, 2002;Marder et al, 2003). This finding can also be understood using the same assumption of functional in vivo intrinsic efficacy of aripiprazole as a partial agonist made earlier to explain lack of motor side effects.…”

Section: Discussionmentioning

confidence: 90%

“…In this context, the introduction of aripiprazole is of interest because while clinically it has all the features of an atypical antipsychotic (antipsychotic effect with very low motor side effects) (Kane et al, 2002;Potkin et al, 2003), it differs from all other antipsychotics in that it is a partial D 2 receptor agonist (Burris et al, 2002). Aripiprazole has been demonstrated to be a partial D 2 agonist in vitro as it acts like an antagonist in the presence of dopamine, while in dopamine's absence it increases dopamine transmission in several cell lines expressing cloned human dopamine D 2L receptors (Lawler et al, 1999;Burris et al, 2002;Shapiro et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…First, unlike other antipsychotics, which lead to clinical efficacy at 60-65% D 2 RO, aripiprazole seems to be effective only at doses which occupy 490% receptors (doses of 15-30 mg/day). Second, despite 490% occupancy, the incidence of EPS in normal volunteers and patients does not exceed that of placebo (Kane et al, 2002;Potkin et al, 2003). Thus, there appears to be a dissociation between the degree to which receptors are blocked (occupancy) and expression of functional antagonism (antipsychotic effects and extrapyramidal side effects) when compared to existing antipsychotic agents.…”

Section: Introductionmentioning

confidence: 99%

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Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Natesan

Reckless

Nóbrega

et al. 2005

Neuropsychopharmacol

176

116

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The novel antipsychotic aripiprazole requires high (490%) striatal D 2 receptor occupancy (D 2 RO) to be clinically active, but despite its high D 2 RO it does not show extrapyramidal symptoms. While most antipsychotics are active at nearly 65% D 2 RO, they show motor side effects when D 2 RO exceeds 80%. We investigated this discrepancy between D 2 RO, 5HT 2 receptor occupancy (5-HT 2 RO) and in vivo functional activity of aripiprazole in comparison to haloperidol (typical) and risperidone (atypical) in animal models. All three drugs showed dose-dependent D 2 RO. While risperidone clearly showed higher 5-HT 2 RO than D 2 RO, aripiprazole and haloperidol showed higher D 2 RO than 5-HT 2 RO at all doses. Haloperidol and risperidone induced catalepsy at doses producing 480% D 2 RO, while aripiprazole despite higher D 2 RO (490%) induced no catalepsy. Haloperidol and risperidone's ED 50 values for inhibition of conditioned avoidance response (CAR) and amphetamine-induced locomotor activity (AIL) corresponded to B60% D 2 RO. In contrast, aripiprazole showed a significant dissociation; while it blocked AIL at similar D 2 RO, a 23-fold higher dose (86% D 2 RO) was required to inhibit CAR. FOS expression in shell region of the nucleus accumbens was significant for all drugs at D 2 ROs that were effective in CAR. However, in the core region of the nucleus accumbens and dorsolateral striatum, aripiprazole differed from the others in that despite high D 2 RO it induced low FOS. Haloperidol and risperidone showed dose/occupancy-dependent prolactin elevations, while aripiprazole did not. Across models, haloperidol and risperidone show similar occupancy-functional antagonism of the D 2 system, while aripiprazole shows a clear dissociation. Partial agonism of aripiprazole offers a good explanation for this dissociation and provides a framework for understanding occupancy-functional relationships of partial D 2 agonist antipsychotics.

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“…Conversely, it has been suggested (Lawler et al, 1999) that aripiprazole is not simply a partial agonist, but a drug whose D 2 functional effects were dependent on the cellular location (and signaling proteins) of the targeted D 2 receptor, a phenomenon termed 'functional selectivity' Lawler et al, 1999;Mottola et al, 2002) or 'agonist trafficking' (Kenakin, 1995). Whatever the mechanism, aripiprazole has been shown to be effective in treating the positive and negative symptoms of schizophrenia with a low incidence of side effects including minimal short-term weight gain, low liability for inducing movement disorders, and reductions (rather than elevations) in plasma prolactin levels (Goodnick and Jerry, 2002;Kane et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology

Shapiro

Renock

Arrington

et al. 2003

Neuropsychopharmacol

845

701

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Atypical antipsychotic drugs have revolutionized the treatment of schizophrenia and related disorders. The current clinically approved atypical antipsychotic drugs are characterized by having relatively low affinities for D 2 -dopamine receptors and relatively high affinities for 5-HT 2A serotonin receptors (5-HT, 5-hydroxytryptamine (serotonin)). Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug that is reported to be a high-affinity D 2 -dopamine receptor partial agonist. We now provide a comprehensive pharmacological profile of aripiprazole at a large number of cloned G protein-coupled receptors, transporters, and ion channels. These data reveal a number of interesting and potentially important molecular targets for which aripiprazole has affinity. Aripiprazole has highest affinity for h5-HT 2B -, hD 2L -, and hD 3 -dopamine receptors, but also has significant affinity

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Efficacy and Safety of Aripiprazole and Haloperidol Versus Placebo in Patients With Schizophrenia and Schizoaffective Disorder

Cited by 538 publications

References 0 publications

Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation

Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation

Dissociation between In Vivo Occupancy and Functional Antagonism of Dopamine D2 Receptors: Comparing Aripiprazole to Other Antipsychotics in Animal Models

Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology

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