Aripiprazole, an Antipsychotic With a Novel Mechanism of Action, and Risperidone vs Placebo in Patients With Schizophrenia and Schizoaffective Disorder

Potkin, Steven G.; Saha, A.; Kujawa, Mary J.; Carson, William H.; Ali, Mirza; Stock, E.; Stringfellow, Joseph; Ингенито, Г.; Marder, Stephen R.

doi:10.1001/archpsyc.60.7.681

Cited by 543 publications

(360 citation statements)

References 25 publications

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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: 79%

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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: 79%

“…(Fleischhacker et al, 2014, Ishigooka et al, 2015Gopal et al, 2011;Turner et al, 2004, Potkin et al, 2003.…”

Section: Discussionmentioning

confidence: 99%

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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“…Evidence from meta-analyses, systematic reviews, individual trials and longer term observational studies has indicated that significant weight gain is seen in many patients receiving psychotropic agents for the treatment of schizophrenia and bipolar disorder. Although no antipsychotic drug can be considered weight-neutral, as weight gain may occur in vulnerable patients during treatment with any atypical antipsychotic, greater mean weight gain does occur with olanzapine and clozapine [62][63][64][65].…”

Section: Plausibilitymentioning

confidence: 99%

Antipsychotic drugs and diabetes—an application of the Austin Bradford Hill criteria

Holt

Peveler

2006

Diabetologia

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There is concern that antipsychotic drugs cause diabetes. Although there has been an explosion in the quantity of literature about this subject, it remains confusing and inconsistent. To assess whether the association between antipsychotic drugs and diabetes is causative, we applied the Austin Bradford Hill criteria to the available evidence. In support of a causative relationship, there is temporality for some cases of diabetes, and there is a biologically plausible explanation. The causative link between antipsychotic drugs and diabetes is coherent with our understanding of diabetes and there are other analogies. However the strength of association is weak, there is lack of consistency or specificity, and there is little evidence to support a biological gradient. We should therefore conclude that the evidence surrounding a causative link between antipsychotic drugs and diabetes is inconclusive. Moreover, the risk is probably low and the attributable risk of developing diabetes is greater for traditional risk factors such as family history, ethnicity, obesity and ageing than it is for receiving an antipsychotic drug. Consequently, the majority of patients receiving second-generation antipsychotics will not develop diabetes as a result of their medication.

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“…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%

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

180

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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Aripiprazole, an Antipsychotic With a Novel Mechanism of Action, and Risperidone vs Placebo in Patients With Schizophrenia and Schizoaffective Disorder

Abstract: Aripiprazole is effective, safe, and well tolerated for the positive and negative symptoms in schizophrenia and schizoaffective disorder. It is the first non-D2 receptor antagonist with clear antipsychotic effects and represents a novel treatment development for psychotic disorders.

Cited by 543 publications

References 25 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

Antipsychotic drugs and diabetes—an application of the Austin Bradford Hill criteria

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

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