The neurocognitive effects of aripiprazole: an open-label comparison with olanzapine

Kern, Robert S.; Green, Michael F.; Cornblatt, Barbara A.; Owen, John; McQuade, Robert D.; Carson, William H.; Ali, Mirza; Marcus, R.

doi:10.1007/s00213-006-0428-x

Cited by 116 publications

(64 citation statements)

References 40 publications

(26 reference statements)

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“…All the AEs were also of mild to moderate severity. The reported AEs (akathisia, insomnia, agitation, sedation and depression) were in keeping with the most common adverse effects found in other clinical trials of aripiprazole in schizophrenia [38,39]. There was a non-significant increase in BARS, mainly due to four patients who reported akathisia.…”

Section: Discussionsupporting

confidence: 84%

An Open-Label Study of Aripiprazole for Methamphetamine Induced Psychosis

Sulaiman

Gill

Said

et al. 2012

Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychophar

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Objective: This study aims to explore the therapeutic effects and tolerability of aripiprazole in the treatment of psychosis among methamphetamine dependence patients. Methods:This was an open label single arm prospective study conducted in University Malaya Medical Centre (UMMC). The study subjects included treatment naïve patients with a current Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) diagnosis of methamphetamine dependence with co-occurrence of acute psychotic symptoms. Eligible patients were treated with an initial dose of 5-10 mg Aripiprazole followed by flexible dose (5-15mg/day) from day 2 to 14. Results:Out of 49 patients enrolled, 41 patients (83.7%) completed the study. At baseline the mean PANSS total score was 79.2 + 13.7 and the mean CGI-S score was 4.3 + 0.5. There was a statistically significant decline in the mean PANSS-total and CGI-S score over the course of the study. The mean reduction was 27.6 ± 21.4 point (p < 0.05, 95% CI [-34.8, -20.4]) from baseline at day 14 for total PANSS score and 2.0 ± 1.2 point (p < 0.05, 95% CI [-2.4, -1.6) for CGI-S. Aripiprazole was generally well tolerated during the study. Adverse events were reported in 10 (20.4%) patients. No statistically significant changes were noted with respect to movement-related adverse events. Conclusions:This study shows that aripiprazole improved the psychotic symptoms associated with methamphetamine use. It was generally well tolerated with mild to moderate adverse events. We conclude that aripiprazole might be an efficacious and safe option for the treatment of methamphetamine induced psychosis.

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Section: Discussionsupporting

confidence: 84%

An Open-Label Study of Aripiprazole for Methamphetamine Induced Psychosis

Sulaiman

Gill

Said

et al. 2012

Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychophar

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“…These findings are in accordance with studies that have shown that atypical antipsychotics may improve cognitive tasks [2,6] . Aripiprazole decreased baseline DNA damage in brain tissue, which suggests a neuroprotective effect, and no cytotoxic or mutagenic effects were detected.…”

Section: Lipoperoxidationsupporting

confidence: 93%

“…Similarly, some investigations have evaluated the effect of antipsychotic drugs on cognitive parameters in humans and animals [4,5] . Research suggests that schizophrenic patients treated with atypical antipsychotics may perform better in cognitive tasks when compared to patients treated with typical antipsychotics [2,6] .…”

Section: Introductionmentioning

confidence: 99%

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Neurobehavioral and genotoxic parameters of antipsychotic agent aripiprazole in mice

et al. 2011

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Aim: Aripiprazole is an antipsychotic agent to treat schizophrenia, which acts through dopamine D 2 partial agonism, serotonin 5-HT 1A partial agonism and 5-HT 2A antagonism. This study was designed to evaluate the neurobehavioral effects and genotoxic/mutagenic activities of the agent, as well as its effects on lipoperoxidation. Methods: Open field and inhibitory avoidance tasks were used. Thirty min before performing the behavioral tasks, adult male CF-1 mice were administered aripiprazole (1, 3 or 10 mg/kg, ip) once for the acute treatment, or the same doses for 5 d for the subchronic treatment. Genotoxic effects were assessed using comet assay in the blood and brain tissues. Mutagenic effects were evaluated using bone marrow micronucleus test. Lipoperoxidation was assessed with thiobarbituric acid reactive substances (TBARS). Results: Acute and subchronic treatments significantly decreased the number of crossing and rearing in the open field task. Acute treatment significantly increased the step-down latency for both the short-and long-term memory in the inhibitory avoidance task. Subchronic treatments with aripiprazole (3 and 10 mg/kg) caused significant DNA strain-break damage in peripheral blood but not in the brain. Mutagenic effect was not detected in the acute and subchronic treatments. Nor TBARS levels in the liver were affected. Conclusion: Aripiprazole improved memory, but could impair motor activities in mice. The drug increased DNA damage in blood, but did not show mutagenic effects, suggesting that it might affect long-term genomic stability.Keywords: antipsychotic agent; aripiprazole; locomotion; memory; genotoxic/mutagenic activities; DNA damage; lipoperoxidation Acta Pharmacologica Sinica (2011Sinica ( ) 32: 1225Sinica ( -1232 doi: 10.1038/aps.2011 published online 15 Aug 2011 Original Article * To whom correspondence should be addressed. [8] .In the experimental context, Nagai et al [9] showed that aripiprazole that was administered as either a single dose or as consecutive doses (for 7 d) ameliorated phencyclidine-induced impairment of recognition memory in mice. However, another study showed that aripiprazole impaired the passiveavoidance response at doses near its anti-dopamine ED 50 (7.7 mg/kg, as defined by apomorphine stereotypy). At doses lower than those that affected the passive-avoidance response, aripiprazole was unable to reverse the MK-801-induced impairment in the same task [4] . Therefore, further investigations are necessary to elucidate the effect of aripiprazole on memory.The aim of the present study was to investigate the effects of aripiprazole on memory and on locomotor and exploratory activities with the inhibitory avoidance and open field tasks as behavioral models. Some drugs that affect memory can induce damage in biomolecules, such as lipids and DNA. Therefore, possible cytotoxic and genotoxic effects were evaluated by measuring lipid peroxidation in the liver and DNA strand breaks in both the peripheral blood and brain tissues after behavioral tasks. Mutagenic e...

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“…Brain imaging studies in schizophrenia patients have shown that AMPH-induced DA release is enhanced in the STR (78) (hyperdopaminergia), whereas a recent study has shown, for the first time, cortical hypodopaminergia in schizophrenia patients (79). Partial agonists, such as ARI, were originally developed to counteract these opposite phenomena but have largely been unsuccessful in correcting cortical dysfunction (80,81). Our behavioral and electrophysiological data show that the ARI-derived βarr2-biased D2R ligand, 94A, can act as a D2R-βarr2 agonist in the PFC but a D2R-βarr2 antagonist on striatal D2 MSNs, highlighting the feasibility of a pharmacological approach, where a drug could potentially simultaneously counteract both the cortical hypodopaminergia with D2R-βarr2 agonism and striatal hyperdopaminergia with D2R-βarr2 antagonism in schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties

Urs

Gee

Pack

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

118

150

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The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyperand hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G proteincoupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies.arrestin | antipsychotics | biased signaling | dopamine D2R | fast-spiking interneurons G protein-coupled receptors (GPCRs) represent the largest family of receptors in the human genome and are one of the most common targets of pharmaceutical drugs (1, 2). Upon ligand binding, GPCRs activate downstream G protein-dependent signaling pathways followed by phosphorylation of the receptor by G protein-coupled receptor kinases (GRKs) (3). Phosphorylation enhances association of the GPCR with β-arrestins (βarrs), and this combined process mediates desensitization of G-protein signaling (4) and internalization of GPCRs (5-7). Two isoforms of βarrs, βarr1 and βarr2, are widely coexpressed in most tissues in mammals and are 80% identical, but they can have either overlapping or distinct functions (8, 9). It is now firmly established that GPCRs activate downstream signaling pathways through not only canonical G-protein pathways but also, the ability of βarrs to scaffold distinct intracellular signaling complexes (10-12). Elucidation of these distinct G-protein and βarr signaling pathways has provided support for the concept of functional selectivity or biased signaling, wherein each signaling pathway has the ability to mediate distinct physiological responses (13). There are now several physiologically relevant examples of selective engagement of signaling pathways or selective GPCR ligands that target these different signaling pathways (13-15). Therefore, leveraging the concept of GPCR functional selectivity holds promise for the development of more selective therapeutic approaches. Dopamine (DA) is a catecholamine neurotransmitter that has been implicated in movement, reward, and cognition (16-19) as well as CNS disorders, such as schizophrenia, attention deficit hyperactivity disorder, Parkinson's disease, and obsessive-compulsive disorder (20-23). DA mediates its effects via GPCRs belonging to two major ...

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The neurocognitive effects of aripiprazole: an open-label comparison with olanzapine

Abstract: The findings from this open-label study suggest that the neurocognitive effects of aripiprazole are at least as good as those of olanzapine.

Cited by 116 publications

References 40 publications

An Open-Label Study of Aripiprazole for Methamphetamine Induced Psychosis

An Open-Label Study of Aripiprazole for Methamphetamine Induced Psychosis

Neurobehavioral and genotoxic parameters of antipsychotic agent aripiprazole in mice

Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties

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