Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials

Marder, Stephen R.; McQuade, Robert D.; Stock, E.; Kaplita, Stephen; Marcus, Ronald N.; Safferman, Allan Z.; Saha, A.; Ali, Mirza; Iwamoto, Taro

doi:10.1016/s0920-9964(03)00050-1

Cited by 419 publications

(318 citation statements)

References 27 publications

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“…There were no other notable features in this individual that could explain the intolerable akathisia. The frequency of extrapyramidal side effects in this sample of children with TD appears to be somewhat higher than expected, compared with the frequency of such symptoms reported in studies of adults with schizophrenia (Marder et al 2003). However, given aripiprazole's partial dopamine agonist-antagonist effects, and the putative therapeutic mechanism of action involving D2 receptor blockade, it is possible that youths with TD, with corticostriato-thalamic-cortical tract disinhibition, may be particularly vulnerable to extrapyramidal side effects of this medication.…”

contrasting

confidence: 75%

Aripiprazole in Children and Adolescents with Tourette's Disorder: An Open-Label Safety and Tolerability Study

Lyon

Samar

Jummani

et al. 2009

Journal of Child and Adolescent Psychopharmacology

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Objective: The aim of this study was to conduct a prospective safety and tolerability study of aripiprazole for the treatment of tics in children and adolescents with Tourette's disorder (TD). Method: Eleven subjects (10 males) with TD (age 9-19 years, mean 13.36, standard deviation [SD] 3.33) who did not respond or were unable to tolerate previous tic medication were treated with aripiprazole in an open-label, flexible-dosing study over 10 weeks. Tic severity was rated using the Yale Global Tic Severity Scale (YGTSS) and the Clinical Global Impressions Scale for tics (CGI-Tics) at baseline and at follow-up. Results: The mean (AESD) daily dose for aripiprazole was 4.5 AE 3.0 mg. Mean (AESD) YGTSS Global Severity scores reduced from 61.82 AE 13.49 at baseline to 33.73 AE 15.18 at end point; mean YGTSS total tic scores reduced from 28.18 AE 7.74 at baseline to 16.73 AE 7.54 at end point. Mean (AESD) CGI-Tic severity scores reduced from 4.45 AE 0.52 (moderate-marked) at baseline to 3.18 AE 0.60 (mild) at end point. On the CGI-Tic improvement scale, 10 (

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contrasting

confidence: 75%

Aripiprazole in Children and Adolescents with Tourette's Disorder: An Open-Label Safety and Tolerability Study

Lyon

Samar

Jummani

et al. 2009

Journal of Child and Adolescent Psychopharmacology

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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: 88%

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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“…Data about changes in glucose concentrations have been presented from 5,607 patients with schizophrenia or schizophreniform illness recruited in 12 prospective randomised clinical trials, of which 11 were double-blind [1,[39][40][41][42][43][44][45][46][47][48][49] (Table 2). Of these studies, eight lasted for at least 6 months and four lasted for more than 1 year.…”

Section: Consistency Of Associationmentioning

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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Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials

Cited by 419 publications

References 27 publications

Aripiprazole in Children and Adolescents with Tourette's Disorder: An Open-Label Safety and Tolerability Study

Aripiprazole in Children and Adolescents with Tourette's Disorder: An Open-Label Safety and Tolerability Study

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

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

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