aripiprazole (Abilify or Abilitat)


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(Updated 1/22/04)

Keck Jr PE, McElroy SL.
Aripiprazole: a partial dopamine D2 receptor agonist antipsychotic.
Expert Opin Investig Drugs. 2003 Apr;12(4):655-62.
"This paper reviews the clinical pharmacology, efficacy and safety of the novel antipsychotic drug aripiprazole. All published citations regarding aripiprazole were reviewed using a Medline((R)) search (completed for citations through mid-year, 2002). In addition, abstracts from recent scientific meetings presenting data not yet published (nor peer-reviewed) were reviewed. Aripiprazole has a unique mechanism of action as a dopamine D2 partial agonist, serotonin 5-HT(1A) partial agonist and serotonin 5-HT(2A) antagonist. Like other new antipsychotics, aripiprazole has the profile of an atypical agent, with efficacy in the treatment of positive and negative symptoms of psychosis as well as mood symptoms, a low rate of neurological side effects and no significant adverse effect on serum prolactin concentrations. In addition, aripiprazole was not associated with significant weight gain or QTc prolongation in both acute and long-term treatment trials." [Abstract]

Ozdemir V, Fourie J, Ozdener F.
Aripiprazole (Otsuka Pharmaceutical Co).
Curr Opin Investig Drugs 2002 Jan;3(1):113-20
"Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-fos mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484]." [Abstract]

Taylor DM.
Aripiprazole: a review of its pharmacology and clinical use.
Int J Clin Pract. 2003 Jan-Feb;57(1):49-54.
"Atypical antipsychotics generally have a lower propensity for extrapyramidal side-effects (EPSE), hyperprolactinaemia and tardive dyskinesia than that associated with typical antipsychotics but may still produce troublesome side-effects, such as weight gain, cardiac rhythm changes and impaired glucose tolerance. Aripiprazole is a new atypical antipsychotic with a unique receptor binding profile that combines partial agonist activity at D2 and 5HT1A receptors with potent antagonism at 5HT2A receptors. Clinical studies in acute schizophrenic relapse, chronic schizophrenia and acute mania show it is robustly more effective than placebo. Once-daily aripiprazole 15-30 mg is as effective as haloperidol 10 mg/day and risperidone 6 mg/day in short-term treatment of schizophrenia and more effective than haloperidol 7-10 mg/day in maintenance of response in chronic schizophrenia. Aripiprazole appears to be well tolerated, with most studies suggesting a frequency of adverse effects similar to placebo. Aripiprazole seems not to cause significant EPSE, hyperprolactinaemia, excessive weight gain or cardiac rhythm disturbance. Limited data suggest that aripiprazole is not associated with impaired glucose tolerance." [Abstract]

Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito G, Marder SR.
Aripiprazole, an Antipsychotic With a Novel Mechanism of Action, and Risperidone vs Placebo in Patients With Schizophrenia and Schizoaffective Disorder.
Arch Gen Psychiatry. 2003 Jul; 60(7): 681-90.
"BACKGROUND: Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This multicenter trial examined the efficacy, safety, and tolerability of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder. METHODS: In this 4-week double-blind study, 404 patients were randomized to 20 mg/d (n = 101) or 30 mg/d (n = 101) of aripiprazole, placebo (n = 103), or 6 mg/d of risperidone (n = 99). Efficacy assessments included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression scores. Safety and tolerability evaluations included extrapyramidal symptoms and effects on weight, prolactin, and corrected QT (QTc) interval. RESULTS: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were significantly better than placebo on all efficacy measures. Separation from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole and risperidone and for PANSS negative scores with aripiprazole. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Mean prolactin levels decreased with aripiprazole but significantly increased 5-fold with risperidone. Mean change in QTc interval did not differ significantly from placebo with any active treatment group. Aripiprazole and risperidone groups showed a similar low incidence of clinically significant weight gain. CONCLUSIONS: 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." [Abstract]

Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW.
Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder.
J Clin Psychiatry. 2002 Sep;63(9):763-71.
"BACKGROUND: Aripiprazole is an investigational agent for treating schizophrenia that has a novel pharmacologic profile. The present study investigated the efficacy, safety, and tolerability of aripiprazole and haloperidol compared with placebo. METHOD: A 4-week, double-blind, randomized study, conducted at 36 U.S. centers between July 1997 and June 1998, compared aripiprazole (15 mg/day, 30 mg/day) to placebo, with haloperidol (10 mg/day) as an active control. Fixed doses of each agent were administered from day 1 throughout the study. A total of 414 patients with a primary DSM-IV diagnosis of schizophrenia or schizoaffective disorder were randomized. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, PANSS-derived Brief Psychiatric Rating Scale (BPRS) core, Clinical Global Impressions (CGI)-Severity of Illness, and mean CGI-Improvement scores. Safety and tolerability evaluations included extrapyramidal symptoms (EPS), weight gain, serum prolactin level, and QTc interval. RESULTS: Both doses of aripiprazole and haloperidol, 10 mg, produced statistically significant (p < or = .05) improvements from baseline in PANSS total, PANSS positive, PANSS-derived BPRS core, and CGI-Severity scores and significantly lower CGI-Improvement scores at endpoint, compared with placebo. Aripiprazole, 15 mg, and haloperidol, 10 mg, significantly improved PANSS negative score compared with placebo. Both aripiprazole doses and haloperidol separated from placebo for PANSS total scores at week 2. Unlike haloperidol, aripiprazole was not associated with significant EPS or prolactin elevation at endpoint compared with placebo. There were no statistically significant differences in mean changes in body weight across the treatment groups versus placebo, and no patients receiving aripiprazole experienced clinically significant increases in QTc interval. CONCLUSION: Aripiprazole, effective against positive and negative symptoms, is a safe and well-tolerated potential treatment for schizophrenia and schizoaffective disorder." [Abstract]

Pigott TA, Carson WH, Saha AR, Torbeyns AF, Stock EG, Ingenito GG; Aripiprazole Study Group.
Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study.
J Clin Psychiatry. 2003 Sep; 64(9): 1048-56.
"BACKGROUND: Aripiprazole is a novel antipsychotic for the management of schizophrenia. This study investigated the efficacy, safety, and tolerability of aripiprazole in preventing relapse in adult chronic schizophrenia patients experiencing ongoing stable symptomatology. METHOD: In this 26-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center study, 310 patients with DSM-IV schizophrenia (mean Positive and Negative Syndrome Scale [PANSS] total score = 82) were randomly assigned to receive a once-daily fixed dose of aripiprazole, 15 mg, or placebo. The primary outcome measure was time to relapse following randomization. Secondary objectives were to assess the efficacy, safety, and tolerability of aripiprazole, 15 mg, compared with placebo, in the study population. The study was conducted between Dec. 21, 2000, and Aug. 20, 2001. RESULTS: The time to relapse following randomization was significantly (p < .001) longer for aripiprazole compared with placebo. More patients relapsed with placebo (N = 85; 57%) than aripiprazole (N = 50; 34%); the relative risk of relapse for the aripiprazole group was 0.59 (p < .001). Aripiprazole was significantly superior to placebo from baseline to endpoint in PANSS total, PANSS positive, PANSS-derived Brief Psychiatric Rating Scale, and Clinical Global Impressions-Severity of Illness scale (CGI-S) scores and demonstrated significantly better mean Clinical Global Impressions-Global Improvement scale scores (p < or = .01 for all comparisons except CGI-S: .01 < p < or = .05). Aripiprazole was well tolerated, with no evidence of marked sedation and no evidence of hyperprolactinemia or prolonged heart rate-corrected QT interval (QTc). Extrapyramidal symptoms were comparable in the aripiprazole and placebo groups. Modest mean weight loss at endpoint was evident in both groups. CONCLUSION: Aripiprazole, 15 mg once daily, is an effective, well-tolerated treatment for prevention of relapse in patients with chronic, stable schizophrenia." [Abstract]

Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, Archibald D, Ingenito G, Marcus R, Pigott T.
Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia.
Int J Neuropsychopharmacol. 2003 Dec; 6(4): 325-37.
"Aripiprazole is a novel atypical antipsychotic for the treatment of schizophrenia. It is a D2 receptor partial agonist with partial agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2A receptors. The long-term efficacy and safety of aripiprazole (30 mg/d) relative to haloperidol (10 mg/d) were investigated in two 52-wk, randomized, double-blind, multicentre studies (using similar protocols which were prospectively identified to be pooled for analysis) in 1294 patients in acute relapse with a diagnosis of chronic schizophrenia and who had previously responded to antipsychotic medications. Aripiprazole demonstrated long-term efficacy that was comparable or superior to haloperidol across all symptoms measures, including significantly greater improvements for PANSS negative subscale scores and MADRS total score (p&0.05). The time to discontinuation for any reason was significantly greater with aripiprazole than with haloperidol (p=0.0001). Time to discontinuation due to adverse events or lack of efficacy was significantly greater with aripiprazole than with haloperidol (p=0.0001). Aripiprazole was associated with significantly lower scores on all extrapyramidal symptoms assessments than haloperidol (p&0.001). In summary, aripiprazole demonstrated efficacy equivalent or superior to haloperidol with associated benefits for safety and tolerability. Aripiprazole represents a promising new option for the long-term treatment of schizophrenia." [Abstract]

Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, Saha A, Ali M, Iwamoto T.
Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials.
Schizophr Res. 2003 Jun 1;61(2-3):123-36.
"Aripiprazole is a novel antipsychotic with a unique mechanism of action. Presented here is a pooled analysis of safety and tolerability data from all completed short-term, placebo-controlled trials in schizophrenia from the aripiprazole clinical development program. Data were analyzed from five 4- to 6-week double-blind multicenter studies of patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder randomized to aripiprazole (n=932), placebo (n=416), or haloperidol (n=201). Daily aripiprazole doses ranged from 2 to 30 mg. Safety assessments included adverse event (AE) reports, EPS scales, ECGs, weight, and prolactin, glucose and cholesterol levels. Aripiprazole was well tolerated, with similar AE incidence rates to placebo, and lower rates than haloperidol for akathisia, extrapyramidal syndrome and somnolence. Objective EPS assessments demonstrated no significant differences between aripiprazole and placebo on Simpson-Angus Scale (SAS) scores, no dose-dependent effects on Barnes Akathisia scores, and significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores from baseline vs. placebo (p</=0.01). Haloperidol showed increased SAS and Barnes Akathisia scores over placebo (p</=0.01). There was minimal mean weight change with aripiprazole (+0.71 kg) and haloperidol (+0.56 kg), and a lack of QT(c) prolongation. Serum prolactin increased with haloperidol, but not aripiprazole. In conclusion, aripiprazole shows a favorable safety and tolerability profile with low potential for EPS, weight gain, prolactin elevation, QT(c) prolongation, and sedation. Aripiprazole's safety profile may offer benefits in schizophrenia treatment." [Abstract]

Goodnick PJ, Jerry JM.
Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder.
J Clin Psychiatry 2002 Sep;63(9):763-71
"BACKGROUND: Aripiprazole is an investigational agent for treating schizophrenia that has a novel pharmacologic profile. The present study investigated the efficacy, safety, and tolerability of aripiprazole and haloperidol compared with placebo. METHOD: A 4-week, double-blind, randomized study, conducted at 36 U.S. centers between July 1997 and June 1998, compared aripiprazole (15 mg/day, 30 mg/day) to placebo, with haloperidol (10 mg/day) as an active control. Fixed doses of each agent were administered from day 1 throughout the study. A total of 414 patients with a primary DSM-IV diagnosis of schizophrenia or schizoaffective disorder were randomized. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, PANSS-derived Brief Psychiatric Rating Scale (BPRS) core, Clinical Global Impressions (CGI)-Severity of Illness, and mean CGI-Improvement scores. Safety and tolerability evaluations included extrapyramidal symptoms (EPS), weight gain, serum prolactin level, and QTc interval. RESULTS: Both doses of aripiprazole and haloperidol, 10 mg, produced statistically significant (p < or = .05) improvements from baseline in PANSS total, PANSS positive, PANSS-derived BPRS core, and CGI-Severity scores and significantly lower CGI-Improvement scores at endpoint, compared with placebo. Aripiprazole, 15 mg, and haloperidol, 10 mg, significantly improved PANSS negative score compared with placebo. Both aripiprazole doses and haloperidol separated from placebo for PANSS total scores at week 2. Unlike haloperidol, aripiprazole was not associated with significant EPS or prolactin elevation at endpoint compared with placebo. There were no statistically significant differences in mean changes in body weight across the treatment groups versus placebo, and no patients receiving aripiprazole experienced clinically significant increases in QTc interval. CONCLUSION: Aripiprazole, effective against positive and negative symptoms, is a safe and well-tolerated potential treatment for schizophrenia and schizoaffective disorder." [Abstract]

Casey DE, Carson WH, Saha AR, Liebeskind A, Ali MW, Jody D, Ingenito GG.
Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study.
Psychopharmacology (Berl). 2003 Apr;166(4):391-9. Epub 2003 Feb 28.
"RATIONALE. Switching patients from one antipsychotic to another can lead to tolerability problems or transient symptom exacerbations. It is important to compare switching strategies to determine which methods produce the best possible patient outcomes. OBJECTIVE. To investigate the efficacy, safety and tolerability of three dosing strategies for switching chronic, stable patients with schizophrenia from current oral antipsychotic monotherapy to once-daily oral aripiprazole monotherapy. METHOD. Patients in this 8-week, open-label, outpatient study were randomized to: 1) immediate initiation of 30 mg/day aripiprazole with simultaneous immediate discontinuation of current antipsychotic; 2) immediate initiation of 30 mg/day aripiprazole while tapering off current antipsychotic over 2 weeks; or 3) up-titrating aripiprazole to 30 mg/day over 2 weeks, while simultaneously tapering off current antipsychotic. Efficacy assessments included PANSS, CGI-S, and CGI-I scores. Safety assessments included: adverse events (AEs) recording, evaluation of extrapyramidal symptoms (EPS), vital signs, ECG, and clinical laboratory tests. RESULTS. Efficacy with aripiprazole was maintained during the study with numerical improvements compared with baseline in all three groups. The overall incidence of AEs was broadly comparable across all groups, and AEs were generally mild to moderate in severity and time-limited. Discontinuations due to AEs were comparable across the groups. No deterioration in EPS occurred in any group. The reduction in body weight and plasma prolactin levels following switch to aripiprazole were comparable across the three groups. CONCLUSION. Any of the three strategies evaluated can be used safely for switching patients to aripiprazole from antipsychotic monotherapy. Furthermore, patients' symptoms may continue to improve after switching to aripiprazole." [Abstract]

Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA.
The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT(1A) receptor.
Eur J Pharmacol 2002 Apr 26;441(3):137-40
"Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone, a novel antipsychotic with partial agonist activity at dopamine D2 receptors, bound with high affinity to recombinant human 5-HT(1A) receptors (h5-HT(1A)) in Chinese hamster ovary cell membranes and displayed potent, partial agonism at 5-HT(1A) receptors in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTP gamma S)-binding assay that was blocked completely by a selective 5-HT(1A) receptor antagonist. An interaction with 5-HT(1A) receptors may contribute to the overall efficacy of aripiprazole against symptoms of schizophrenia, including anxiety, depression, cognitive and negative symptoms, and to its favorable side-effect profile. Combined with previous studies demonstrating the potent partial agonism of aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is the first dopamine-serotonin system stabilizer." [Abstract]

Goodnick PJ, Rodriguez L, Santana O.
Antipsychotics: impact on prolactin levels.
Expert Opin Pharmacother 2002 Oct;3(10):1381-91
"Hyperprolactinaemia has been associated with a variety of side effects including amenorrhoea, galactorrhoea, sexual dysfunction, breast engorgement and osteoporosis. Since the mid-1970s, the impact of antipsychotics on human prolactin (hPrl) levels has been investigated. Baseline levels of hPrl were found to be similar in healthy controls and patients who were diagnosed as having schizophrenia. Short-term acute studies done after single parenteral or oral doses of phenothiazines found rapid two- to tenfold increases in hPrl. Similar increases were found in longer term studies that reported increases of three times in both men and women after 3 days that doubled again after several weeks of treatment. A study of longer term injectable fluphenazine enanthate found that elevation induced by a single injection lasted up to 28 days. The same results with significant increases have been reported with the butyrophenone, haloperidol. Substantial increases are found after single injections (up to nine times) and after weeks of treatment (up to three times sustained). Thus, early literature believed that there might be an association between these induced changes and response to therapy. However, prolactin is secreted by the anterior pituitary and is under inhibitory control of dopamine released from the tuberoinfundibular neurones. Thus, increases in prolactin are due to antipsychotic impact on tuberoinfundibular tract, one of four dopamine-related tracts. With the application of clozapine and other atypical antipsychotics, it was found that medications can successfully treat psychosis without increasing hPrl. In fact, early single-dose trails found clozapine to reduce hPrl by 16%. Later studies replicated this result and also found that up to 6 weeks of administration led to reductions in hPrl of up to 80%. Risperidone, however, has been found to persistently elevate hPrl in studies, despite its impact on other receptor sites. Olanzapine, quetiapine and ziprasidone have all been found to have little effect or produce decreases in hPrl. Most recently, aripiprazole, in early studies, appears to produce significant reductions in hPrl while maintaining therapeutic efficacy for psychosis." [Abstract]

Canive JM, Lewine JD, Edgar JC, Davis JT, Miller GA, Torres F, Tuason VB.
Spontaneous brain magnetic activity in schizophrenia patients treated with aripiprazole.
Psychopharmacol Bull 1998;34(1):101-5
"This magnetoencaphalographic (MEG) study was conducted as part of a multicenter clinical trial to study the efficacy of aripiprazole. Participants included 5 DSM-IV schizophrenia subjects and 10 age-matched normal controls. The schizophrenia subjects underwent a second MEG recording after 8 weeks of open-label treatment with aripiprazole. Overall, control subjects showed no abnormal spontaneous magnetic brain activity. At washout, 3 patients showed increased delta and theta activity along with paraxosymal bitemporal slow waves. In 2 of these patients, the slow waves were generated in the superior temporal plane, as determined by dipole modeling. In the third patient, the slow waves appeared to have been generated at multiple regions throughout the temporal and inferior parietal lobes. As a group, schizophrenia patients, when compared with normal controls, demonstrated significant decreases in alpha peak frequency and power. Following treatment, aripiprazole had a significant normalizing effect on delta and theta activity. Patients on aripiprazole continued to demonstrate significant abnormalities in alpha frequency and power." [Abstract]

Jordan S, Koprivica V, Dunn R, Tottori K, Kikuchi T, Altar CA.
In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function.
Eur J Pharmacol. 2004 Jan 1; 483(1): 45-53.
"In vivo microdialysis was used to monitor the effects of oral aripiprazole and olanzapine on basal extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) in the medial prefrontal cortex and striatum of conscious, freely moving rats. Acute aripiprazole administration did not affect dopamine output, but produced moderate increases in DOPAC and HVA concentrations, in medial prefrontal cortex or striatum of drug-nai;ve rats. Similarly, aripiprazole did not affect dopamine output but produced moderate elevations in DOPAC and HVA concentrations in the striatum of chronic aripiprazole-pretreated rats. Olanzapine produced comparatively larger elevations in dopamine, DOPAC, and HVA in both regions, which, in the striatum, were diminished after chronic olanzapine exposure. Aripiprazole reduced extracellular 5-HIAA concentrations in the medial prefrontal cortex and striatum of drug-nai;ve rats, but not in chronic aripiprazole-pretreated rats. Together, these data provide in vivo evidence of aripiprazole-induced changes in forebrain dopaminergic and serotonergic function that may reflect its partial agonist activity at presynaptic dopamine D(2) and 5-HT(1A) receptors and antagonist activity at 5-HT(2A) receptors." [Abstract]

Nakai S, Hirose T, Uwahodo Y, Imaoka T, Okazaki H, Miwa T, Nakai M, Yamada S, Dunn B, Burris KD, Molinoff PB, Tottori K, Altar CA, Kikuchi T.
Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone.
Eur J Pharmacol. 2003 Jul 4; 472(1-2): 89-97.
"Catalepsy and changes in striatal and limbic dopamine metabolism were investigated in mice after oral administration of aripiprazole, haloperidol, and risperidone. Catalepsy duration decreased with chronic (21 day) aripiprazole compared with acute (single dose) treatment across a wide dose range, whereas catalepsy duration persisted with chronic haloperidol treatment. At the time of maximal catalepsy, acute aripiprazole did not alter neostriatal dopamine metabolite/dopamine ratios or homovanillic acid (HVA) levels, and produced small increases in dihydroxyphenylacetic acid (DOPAC). Effects were similar in the olfactory tubercle. Dopamine metabolism was essentially unchanged in both regions after chronic aripiprazole. Acute treatments with haloperidol or risperidone elevated DOPAC, HVA, and metabolite/dopamine ratios in both brain areas and these remained elevated with chronic treatment. The subtle effects of aripiprazole on striatal and limbic dopamine metabolism, and the decrease in catalepsy with chronic administration, illustrate fundamental differences in dopamine neurochemical actions and behavioral sequelae of aripiprazole compared to haloperidol or risperidone." [Abstract]

Semba J, Sakai M, Miyoshi R, Mataga N, Fukamauchi F, Kito S.
Differential expression of c-fos mRNA in rat prefrontal cortex, striatum, N. accumbens and lateral septum after typical and atypical antipsychotics: an in situ hybridization study.
Neurochem Int 1996 Oct;29(4):435-42
"The regional difference in the expression of c-fos mRNA induced by typical and atypical antipsychotics was determined in prefrontal cortex, striatum, N. accumbens and lateral septum in rats by in situ hybridization. Two typical antipsychotics, haloperidol (2 mg/kg) and fluphenazine (2 mg/kg), and three atypical antipsychotics, (-)sulpiride (100 mg/kg), clozapine (20 mg/kg) and OPC-14597 (40 mg/kg), were used. Brains were fixed with 4% paraformaldehyde 45 min after drug administration (i.p.). Brain sections of 30 microns-thickness were made in a cryostat and hybridized with 35S-labelled for c-fos oligonucleotide probe. These sections were apposed to X-ray films and the autoradiograms were semi-quantitatively analysed by computer-assisted densitometry. All antipsychotics used increased c-fos mRNA expression in N. accumbens shell, a region of the forebrain associated with limbic systems. On the other hand, two typical antipsychotics (haloperidol and fluphenazine) that cause a high incidence of acute motor side effects increased the expression of c-fos mRNA in the dorsolateral striatum, an extrapyramidal region primarily involved in motor control. Only clozapine induced c-fos mRNA in the medial prefrontal cortex and lateral septum. These results strongly suggest that the shell region of N. accumbens may be a common site of therapeutic action of antipsychotics." [Abstract]

Yamada S, Harano M, Yokoo H, Tanaka M.
Antagonistic effects of OPC-14597, a novel antipsychotic drug, on quinpirole- and (-)-sulpiride-induced changes in evoked dopamine release in rat striatal slices.
J Pharm Pharmacol 1997 Feb;49(2):206-8
"The effects of a newly synthesized quinolinone derivative, 7-[4-(4-(2,3-dichlorophenyl)-1-piperazinyl) butoxy)-3,4-dihydro-2-(1H)-quinolinone (OPC-14597), a novel antipsychotic drug, on electrically evoked dopamine release in rat striatal slices were investigated. OPC-14597 (0.1-10 microM) had no effect on the dopamine release evoked in the striatal slices. The decrease induced by quinpirole, a dopamine receptor agonist, in evoked dopamine release was attenuated by superfusion with OPC-14597 (1 and 10 microM) which by itself had no effect on evoked dopamine release. The increase induced by (-)-sulpiride, a dopamine receptor antagonist, in evoked dopamine release was, moreover, also attenuated by 1 and 10 microM OPC-14597. These findings indicate that OPC-14597 antagonizes both dopamine agonist- and antagonist-induced changes in evoked dopamine release in striatal slices in rats." [Abstract]

Momiyama T, Amano T, Todo N, Sasa M.
Inhibition by a putative antipsychotic quinolinone derivative (OPC-14597) of dopaminergic neurons in the ventral tegmental area.
Eur J Pharmacol 1996 Aug 22;310(1):1-8
"The effects of the newly synthesized quinolinone derivative, OPC-14597 (7- inverted question mark4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy inverted question mark-3, 4-dihydro-2(1 H)-quinolinone), on dopaminergic neuronal activity in the ventral tegmental area were examined using both in vivo microiontophoretic methods in chloral hydrate-anesthetized rats and the tight-seal whole-cell patch-clamp technique in thin-slice preparations of the rat brain. Neurons in the ventral tegmental area were classified as type I or type II according to their responses to antidromic stimulation of the nucleus accumbens, probably corresponding to dopaminergic and non-dopaminergic neurons, respectively. Antidromic spikes elicited by nucleus accumbens stimulation were inhibited by microiontophoretic application of dopamine and OPC-14597 in type I, but not in type II neurons. Although the OPC-14597-induced inhibition was antagonized by simultaneous application of domperidone (5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1 H-benzimidazo-1-yl)-propy]-4-piperidinyl]-1,3-dihydro-2H- benzimidazol-2-one; dopamine D2 receptor antagonist), SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1 H-3-benzazepine hydrochloride; dopamine D1 receptor antagonist) had no such effect. Spontaneous firing of type I neurons was also inhibited by iontophoretically applied OPC-14597 and dopamine, whereas that of type II neurons was unaffected. The inhibitory effect of OPC-14597 on the spontaneous firing of type I neurons was antagonized by domperidone, but not by SCH 23390. In a whole-cell patch-clamp study using a thin-slice preparation of the rat brain, bath application of OPC-14597 induced hyperpolarization accompanied by inhibition of spontaneously occurring action potentials in the large neurons (> 20 microns in diameter) in a concentration-dependent manner. These results suggest that OPC-14597 acts on dopaminergic neurons in the ventral tegmental area as a dopamine D2 receptor agonist to inhibit neuronal activities, probably by increasing membrane potassium conductance." [Abstract]

Stahl SM.
Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 1, "Goldilocks" actions at dopamine receptors.
J Clin Psychiatry 2001 Nov;62(11):841-2
"Dopamine system stabilizers are a potential new class of antipsychotic agents without motor side effects. All known effective antipsychotics act at D2 receptors. A novel concept for an antipsychotic without motor side effects is to stabilize these receptors rather than block them harshly." [Abstract]

McGavin JK, Goa KL.
CNS Drugs 2002;16(11):779-86; discussion 787-8
"Aripiprazole is a quinolinone derivative and the first of a new class of atypical antipsychotics. The drug has partial agonist activity at dopamine D(2) and serotonin 5-HT(1A) receptors, and is also an antagonist at 5-HT(2A) receptors. In patients with acute relapse of schizophrenia or schizoaffective disorder, aripiprazole 15 to 30 mg/day was at least as effective as haloperidol 10 mg/day and had similar efficacy to risperidone 6 mg/day in well designed, 4-week, placebo-controlled trials. Negative symptoms improved earlier in the aripiprazole than the risperidone group. Efficacy of aripiprazole was observed at week 1 in several trials and was sustained throughout the study periods. Aripiprazole was superior to placebo in a 26-week trial in patients with stable, chronic schizophrenia. In a 52-week trial involving patients with acute relapsing disease, aripiprazole was similar to haloperidol as assessed by time to failure to maintain response and was superior in ameliorating negative and depressive symptoms. The incidence of extrapyramidal symptoms during aripiprazole therapy was similar to that with risperidone and placebo but lower than with haloperidol. Compared with placebo, the proportion of patients with increased plasma prolactin levels and QTc prolongation was similar in patients treated with aripiprazole 15 to
30 mg/day but was significantly increased with haloperidol and risperidone." [Abstract]

Winans E.
Am J Health Syst Pharm. 2003 Dec 1; 60(23): 2437-45.
"The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of aripiprazole are discussed. Aripiprazole is a third-generation antipsychotic agent indicated for use in the treatment of schizophrenia. Unlike other antipsychotics, aripiprazole demonstrates mixed D2 and serotonin (5-HT1A) receptor agonist-antagonist activity that is hypothesized to improve schlzophrenia's positive and negative symptoms; the drug has been referred to as a dopamine-serotonin stabilizer. Aripiprazole is well absorbed, with peak plasma concentrations occurring within three to five hours after administration. The oral availability is 87%. The mean elimination half-life is about 75 hours for aripiprazole and 94 hours for its active metabolite. In controlled, randomized, multicenter trials, aripiprazole has demonstrated efficacy in the treatment of schizophrenia comparable to that of haloperidol and superior to placebo. In a single clinical trial, aripiprazole was superior to placebo in the treatment of acute mania. The most frequent adverse effects are headache, anxiety, insomnia, nausea, vomiting, and lightheadedness. Because aripiprazole is a substrate of both cytochrome P-450 isoenzymes 3A4 and 2D6, there is a potential for other drugs to affect its metabolism. The recommended starting dosage is 10 or 15 mg daily, preferably administered with meals. Aripiprazole offers an alternative to second-generation antipsychotic agents in the treatment of schizophrenia." [Abstract]

Goodnick PJ, Jerry JM.
Aripiprazole: profile on efficacy and safety.
Expert Opin Pharmacother 2002 Dec;3(12):1773-81
"Aripiprazole (Abilitat trade mark, Bristol-Myers Squibb) is the most recent addition to the new class of atypical antipsychotic medications, following the release of clozapine, risperidone, olanzapine, quetiapine and ziprasidone. Aripiprazole exhibits typical antagonism at dopamine (D2) receptors in the mesolimbic pathway, as well as having unique partial agonist activity at D2 receptors in the mesocortical pathway. As exemplified by other atypical antipsychotics, it displays strong 5-HT(2a) receptor antagonism and is similar to ziprasidone in also having agonistic activity at the 5-HT(1a) receptor. Among the atypical antipsychotics, aripiprazole displays the lowest affinity for alpha(1)adrenergic (alpha(1)), histamine (H1) and muscarinic (M1) receptors. This combination of effects may be responsible for its efficacy in positive and negative symptoms of schizophrenia and in bipolar disorder. Similarly, this profile may be the reason for the low rates of reported side effects observed. This includes general adverse events, a low incidence of reported weight gain and a low liability for inducing movement disorders. Other early data suggest that aripiprazole may induce reductions in plasma prolactin, as well as in plasma glucose and lipid profiles. Finally, results also support the proposition that aripiprazole may lead to reductions in corrected QT interval and have minimal drug interactions." [Abstract]

Keck PE Jr, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G; Aripiprazole Study Group.
A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania.
Am J Psychiatry. 2003 Sep;160(9):1651-8.
"OBJECTIVE: The authors compared the efficacy and safety of aripiprazole, a novel antipsychotic, to placebo for treatment of patients in an acute manic or mixed episode of bipolar disorder. METHOD: This 3-week, multicenter, double-blind study randomly assigned 262 bipolar disorder patients in an acute manic or mixed episode to aripiprazole, 30 mg/day (reduced to 15 mg/day if needed for tolerability), or placebo. Patients remained hospitalized for at least 2 of the weeks. The primary efficacy measure was mean change from baseline in total score on the Young Mania Rating Scale; response was defined as a decrease in score of > or =50%. RESULTS: Aripiprazole produced statistically significant mean improvements in total score on the Young Mania Rating Scale compared with placebo (-8.2 versus -3.4, respectively) and produced a significantly higher response rate (40% versus 19%). For key efficacy variables (response per Young Mania Rating Scale; Clinical Global Impression-Bipolar Version scores for severity of illness [mania] and change from preceding phase [mania]), aripiprazole separated from placebo by day 4. The completion rate was significantly higher with aripiprazole than with placebo (42% versus 21%). Discontinuations due to adverse events did not differ significantly between the aripiprazole and placebo groups. There were no significant changes in body weight versus placebo, and aripiprazole was not associated with elevated serum prolactin or QTc prolongation. CONCLUSIONS: Aripiprazole had significantly greater efficacy than placebo for the treatment of bipolar disorder patients in acute manic or mixed episodes and was safe and well tolerated in this randomized controlled trial." [Abstract]

Tamminga CA.
Partial dopamine agonists in the treatment of psychosis.
J Neural Transm 2002 Mar;109(3):411-20
"The discovery and characterization of dopamine in the mammalian brain earned Dr. Arvid Carlsson the Nobel Prize in 2000. Along with his many insights about dopamine pharmacology, came his proposal of the existence and critical role of dopamine autoreceptors in the overall regulation of dopamine-mediated neurotransmission. In this paper, the rationale, the putative mechanisms, and pertinent clinical data are reviewed to support the idea of the clinical relevance of dopamine agonists, especially partial agonists, in the treatment of psychosis. Evidence was gathered for the usefulness of this strategy in schizophrenia in early trials with apomorphine and N-propylnoraporphine (NPA). But clinical relevance was not a reality before the application of (-)-3PPP. These clinical results are presented. Moreover, now a partial dopamine agonist, aripiprazole, has been developed and will likely be marketed by BMS and Otsuka for the treatment of psychosis and will be the first drug in this class to be commercially available. Partial dopamine agonists represent the next new class of antipsychotic drugs, effective in treating schizophrenia." [Abstract]

Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB.
Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes.
Neuropsychopharmacology. 1999 Jun;20(6):612-27.
"OPC-14597 inverted question markaripiprazole; 7-(-4(4-(2,3-dichlorophenyl)-1-piperazinyl) butyloxy)-3,4-dihydro-2(1H)-quinolinone inverted question mark is a novel candidate antipsychotic that has high affinity for striatal dopamine D2-like receptors, but causes few extrapyramidal effects. These studies characterized the molecular pharmacology of OPC-14597, DM-1451 (its major rodent metabolite), and the related quinolinone derivative OPC-4392 at each of the cloned dopamine receptors, and at serotonin 5HT6 and 5HT7 receptors. All three compounds exhibited highest affinity for D2L and D2S receptors relative to the other cloned receptors examined. Both OPC-4392 and OPC-14597 demonstrated dual agonist/antagonist actions at D2L receptors, although the metabolite DM-1451 behaved as a pure antagonist. These data suggest that clinical atypicality can occur with drugs that exhibit selectivity for D2L/D2S rather than D3 or D4 receptors, and raise the possibility that the unusual profile of OPC-14597 in vivo (presynaptic agonist and postsynaptic antagonist) may reflect different functional consequences of this compound interacting with a single dopamine receptor subtype (D2) in distinct cellular locales." [Abstract]

Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R.
Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology.
Neuropsychopharmacology. 2003 May 21 [Epub ahead of print].
"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 (5-30 nM) for several other 5-HT receptors (5-HT(1A), 5-HT(2A), 5-HT(7)), as well as alpha(1A)-adrenergic and hH(1)-histamine receptors. Aripiprazole has less affinity (30-200 nM) for other G protein-coupled receptors, including the 5-HT(1D), 5-HT(2C), alpha(1B)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, and beta(2)-adrenergic, and H(3)-histamine receptors. Functionally, aripiprazole is an inverse agonist at 5-HT(2B) receptors and displays partial agonist actions at 5-HT(2A), 5-HT(2C), D(3), and D(4) receptors. Interestingly, we also discovered that the functional actions of aripiprazole at cloned human D(2)-dopamine receptors are cell-type selective, and that a range of actions (eg agonism, partial agonism, antagonism) at cloned D(2)-dopamine receptors are possible depending upon the cell type and function examined. This mixture of functional actions at D(2)-dopamine receptors is consistent with the hypothesis proposed by Lawler et al (1999) that aripiprazole has 'functionally selective' actions. Taken together, our results support the hypothesis that the unique actions of aripiprazole in humans are likely a combination of 'functionally selective' activation of D(2) (and possibly D(3))-dopamine receptors, coupled with important interactions with selected other biogenic amine receptors-particularly 5-HT receptor subtypes (5-HT(1A), 5-HT(2A))." [Abstract]

Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF.
Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride.
Neuropsychopharmacology. 2002 Aug;27(2):248-59.
"Aripiprazole (OPC 14597) is an antipsychotic drug that has high affinity for dopamine D2 and D3 receptors and the dopamine autoreceptor. It is being developed for treatment of patients with schizophrenia. The purpose of this study was to determine whether a dose response following graduated doses of aripiprazole could be quantified and correlated with its occupancy of the D2 and D3 dopamine receptors in the brain of living humans. Dopamine D2 and D3 receptor occupancy in fifteen normal male human brains was measured using positron emission tomography (PET) with [11C]raclopride. PET studies were performed before and after two weeks of administration of aripiprazole. The dopamine D2 receptor occupancy was quantified with two kinetic modeling methods without using a blood input function. Administration of aripiprazole for 14 days resulted in a dose-dependent receptor occupancy between 40 - 95% after the administration of 0.5mg, 1 mg, 2 mg, 10 mg, and 30 mg per day. These results suggest that an adequate occupancy can be obtained, and this may be useful to predict an appropriate therapeutic dose for an individual patient. Interestingly, even at striatal D2 receptor occupancy values above 90%, which occurred with the higher doses, extrapyramidal side effects (EPS) were not observed. This underlines aripiprazole's unique mechanism of action as a partial dopamine receptor agonist, which might become a novel principle in the treatment of schizophrenia." [Abstract]

Grunder G, Carlsson A, Wong DF.
Mechanism of new antipsychotic medications: occupancy is not just antagonism.
Arch Gen Psychiatry. 2003 Oct; 60(10): 974-7.
"Antagonism of D2-like dopamine receptors is the putative mechanism underlying the antipsychotic efficacy of psychotropic drugs. Positron emission tomographic studies suggest that the antipsychotic effect of dopamine receptor antagonists occurs within a therapeutic window between 60% and 80% (striatal) D2 receptor occupancy. The incidence of extrapyramidal side effects increases above the 80% threshold. However, the novel atypical antipsychotic drug, aripiprazole, occupies up to 95% of striatal D2-like dopamine receptors at clinical doses, and the incidence of extrapyramidal side effects with aripiprazole is no higher than with placebo. The most likely explanation for this finding is aripiprazole's weak partial agonism at D2-like dopamine receptors. This particular pharmacologic feature characterizes a new class of atypical antipsychotics that does not match the original concept of a therapeutic occupancy window for antagonist antipsychotics. When not involving pure antagonists, it implies a need to adjust the expected receptor occupancy (measured using positron emission tomography) for the therapeutic window." [Abstract]

Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB.
Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors.
J Pharmacol Exp Ther 2002 Jul;302(1):381-9
"Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans." [Abstract]

Meltzer HY, Li Z, Kaneda Y, Ichikawa J.
Serotonin receptors: their key role in drugs to treat schizophrenia.
Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct; 27(7): 1159-72.
"Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them." [Abstract]

Inoue A, Miki S, Seto M, Kikuchi T, Morita S, Ueda H, Misu Y, Nakata Y.
Aripiprazole, a novel antipsychotic drug, inhibits quinpirole-evoked GTPase activity but does not up-regulate dopamine D2 receptor following repeated treatment in the rat striatum.
Eur J Pharmacol 1997 Feb 19;321(1):105-11
"Aripiprazole, a quinolinone derivative, is a new dopaminergic agent which has been recently developed and demonstrated to be clinically useful as an antipsychotic drug with reduced extrapyramidal motor side effects. Here, we found that aripiprazole competed [3H]spiperone binding with a 100-fold higher affinity than [3H]SCH23390 binding, and inhibited the quinpirole-induced facilitation of high-affinity GTPase activity in rat striatal membranes. The effects of chronic administration of aripiprazole and haloperidol on dopamine D2 receptor binding and mRNA level in rat striata were examined by a [3H]spiperone binding assay and a ribonuclease protection assay. Haloperidol induced a significant rise in Bmax of [3H]spiperone binding at 1 mg/kg and in the level of dopamine D2L receptor mRNA at 4 mg/kg. A high dose of aripiprazole (100 mg/kg) only tended to increase the Bmax of [3H]spiperone binding non-significantly, and had no effect on the level of dopamine D2L receptor mRNA. These results indicated that aripiprazole had an antagonistic activity to dopamine D2 receptors with a high affinity, but that the potency of aripiprazole to up-regulate dopamine D2 receptors in the striatum was much smaller than that of haloperidol. This small up-regulation may be related to the ability to aripiprazole to act without side effects including tardive dyskinesia." [Abstract]

Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, Morita S.
7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity.
J Pharmacol Exp Ther 1995 Jul;274(1):329-36
"The effects of 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2 (1H)- quinolinone (OPC-14597), a derivative of the dopamine (DA) autoreceptor agonist 7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone (OPC-4392), on DA receptors were biochemically and behaviorally studied and compared with those of OPC-4392. Both OPC-14597 and OPC-4392 inhibited reserpine- and gamma-butyrolactone (GBL)-induced increase in tyrosine hydroxylase activity in the mouse and rat brain. The effects of OPC-14597 were comparable to those of OPC-4392 and were completely antagonized by haloperidol. OPC-14597, unlike apomorphine, did not evoke postsynaptic DA receptor-stimulating behavioral signs such as hyperlocomotion in the reserpinized mice and contralateral rotation in rats with unilateral striatal 6-hydroxydopamine lesions. Both OPC-14597 and OPC-4392 inhibited such apomorphine-induced postsynaptic behavioral changes as stereotypy and hyperlocomotion in mice and rats and rotation in rats with unilateral striatal kainic acid lesions. The anti-apomorphine effects of OPC-14597 were about 30 to 140 times greater than those of OPC-4392 and were observed at doses that inhibit the increases in tyrosine hydroxylase activity. The affinities of OPC-14597 for 3H-spiperone-labeled D2 receptors in the rat frontal cortex, limbic forebrain and striatum were higher than those of OPC-4392. These results suggest that OPC-14597 is a unique antipsychotic drug candidate, being a DA autoreceptor agonist that has a stronger postsynaptic D2 receptor antagonistic activity than that of OPC-4392." [Abstract]

Inoue A, Seto M, Sugita S, Hide I, Hirose T, Koga N, Kikuchi T, Nakata Y.
Differential effects on D2 dopamine receptor and prolactin gene expression by haloperidol and aripiprazole in the rat pituitary.
Brain Res Mol Brain Res 1998 Apr;55(2):285-92
"[3H]Spiperone-binding assay to D2 receptors and quantitative ribonuclease protection assay for both isoforms (D2L and D2S receptor) of the D2 receptor mRNA and the prolactin mRNA were performed on pituitaries from the control rat and from the rat injected orally daily with either haloperidol (2 mg/kg) or aripiprazole (24 mg/kg) for 21 days. Haloperidol treatment increased the [3H]spiperone-binding by 28%, the levels of D2L and D2S receptor mRNA by 41% and 38%, respectively, and the level of prolactin mRNA by 26%. In contrast, the treatment with aripiprazole, a newly developed atypical antipsychotic with reduced side effects, decreased the [3H]spiperone-binding by 24% and the levels of D2L and D2S receptor mRNA by 23% and 23%, respectively, and did not have any effect on the level of prolactin mRNA. The same treatment with sulpiride (100 mg/kg) increased the levels of D2L and D2S receptor mRNA by 59% and 62%, respectively, but treatment with clozapine (25 mg/kg) did not cause any effect. Neither treatment changed the ratio of the level of D2S receptor mRNA to the level of D2L receptor mRNA in the pituitary. These findings indicate that D2 receptor densities in the pituitary are influenced differentially by the treatment with these antipsychotics, which could be induced at least partly by the changes in the levels of mRNA without any effects on the splicing mechanisms and thus affect the plasticity of the prolactin mRNA expression." [Abstract]

Inoue T, Domae M, Yamada K, Furukawa T.
Effects of the novel antipsychotic agent 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro -2(1H)-quinolinone (OPC-14597) on prolactin release from the rat anterior pituitary gland.
J Pharmacol Exp Ther 1996 Apr;277(1):137-43
"The effects of a novel antipsychotic agent, 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2 (1H)-quinolinone (OPC-14597, generic name aripiprazole), on prolactin (PRL) release from isolated rat anterior pituitary slices and on the serum PRL levels were investigated in male rats. In in vitro experiments on the isolated anterior pituitary, the spontaneous PRL release was decreased by talipexole, a dopamine D2 receptor full agonist, in a dose-dependent manner to 36% of the basal release, and the decrease was antagonized by haloperidol, a D2 receptor antagonist. OPC-14597 also decreased the release of PRL at the same concentration range with a maximal decrease to 78%, the potency being weaker than that of talipexole. The decrease in PRL release induced by OPC-14597 was completely antagonized by haloperidol. Moreover, OPC-14597 antagonized the inhibition of PRL release induced by talipexole. In in vivo experiments, haloperidol increased the serum PRL levels to 8 times the basal PRL level, whereas talipexole decreased the levels to 49% of the basal level. OPC-14597 increased the serum PRL levels by 2-fold and also antagonized the talipexole-induced decrease. The hyperprolactinemia induced by estrogen, which was inhibited by talipexole but enhanced by haloperidol, was enhanced by OPC-14597, whereas the hyperprolactinemia induced by reserpine, which was inhibited by talipexole but elevated by haloperidol, was inhibited by OPC-14597. In addition, the OPC-14597-induced inhibition was antagonized by haloperidol. These results suggest that OPC-14597 has a mixed agonist/antagonist profile at D2 receptors on lactotroph cells and thereby exerts either an antagonistic or an agonistic action, depending on the preexisting tone of the dopaminergic neuronal activities." [Abstract]

Sugiyama A, Satoh Y, Hashimoto K.
In vivo canine model comparison of cardiohemodynamic and electrophysiological effects of a new antipsychotic drug aripiprazole (OPC-14597) to haloperidol.
Toxicol Appl Pharmacol 2001 Jun 1;173(2):120-8
"The cardiovascular effects of aripiprazole were assessed in comparison with those of haloperidol using a halothane-anesthetized canine model with monophasic action potential monitoring. Aripiprazole (n = 6) or haloperidol (n = 6) was infused over 10 min at escalating doses of 0.03, 0.3, and 3.0 mg/kg with intervals of 20 min between doses. Clinically relevant plasma concentrations were obtained after 0.03-0.3 mg/kg of aripiprazole as well as haloperidol. After 0.03-0.3 mg/kg of aripiprazole, positive chronotropic, inotropic, and dromotropic effects, shortening of the ventricular effective refractory period (ERP) and repolarization phase, and decrease of total peripheral resistance were observed in a dose-related manner. However, in the presence of a beta-blocking dose of esmolol (0.1 mg/kg/min), these changes were not induced. After 3.0 mg/kg of aripiprazole administration, cardiac effects induced by the lower doses were attenuated or disappeared, while the negative chronotropic, dromotropic, and hypotensive actions and prolongation of ERP and repolarization phase were induced. After 0.03 mg/kg of haloperidol, no significant change was observed, except for the decrease of the peripheral resistance. After 0.3-3.0 mg/kg of haloperidol, negative chronotropic, inotropic, and hypotensive actions, intraventricular conduction delay, and prolongation of ventricular ERP and repolarization phase were observed in a dose-related manner accompanied by further decrease of the peripheral resistance. The inhibitory effects of aripiprazole on cardiovascular parameters in dogs were less potent than those of haloperidol at clinically relevant exposures, moreover, aripiprazole, unlike haloperidol, neither induced early afterdepolarization nor prolonged the ventricular electrical vulnerable period. Therefore, aripiprazole can be considered safer to use than haloperidol." [Abstract]


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Recent Aripiprazole Research

1) Nagasaka Y, Oda K, Iwatsubo T, Kawamura A, Usui T
Effects of aripiprazole and its active metabolite dehydroaripiprazole on the activities of drug efflux transporters expressed both in the intestine and at the blood-brain barrier.
Biopharm Drug Dispos. 2012 Jul 27;
The inhibition potencies of aripiprazole and its active metabolite, dehydroaripiprazole, on the activities of human multidrug resistance protein 1 (MDR1/ABCB1; P-glycoprotein), breast cancer resistance protein (BCRP/ABCG2), and multidrug resistance-associated protein 4 (MRP4/ABCC4), that are drug efflux transporters expressed both in the intestine and at the blood brain barrier (BBB), were investigated. Aripiprazole and dehydroapripiprazole showed relatively strong inhibitory effects on human MDR1 with IC(50) values of 1.2 and 1.3 ?M in human MDR1-transfected Mardin-Darby canine kidney (MDCKII-MDR1) cells, respectively. The inhibition potencies of other atypical antipsychotics (risperidone, paliperidone, olanzapine, and ziprasidone) for human MDR1 were also evaluated using the same in vitro experimental system and IC(50) values were more than 10-fold higher than those of the two compounds. Aripiprazole and dehydroaripiprazole also had inhibition potencies against human BCRP with IC(50) values of 3.5 and 0.52 ?M, respectively. The ratios of steady-state unbound concentrations of aripiprazole and dehydroaripiprazole to their IC(50) values against human MDR1 and BCRP activities were less than 0.1, whereas the theoretically maximum gastrointestinal concentration of aripiprazole ([I](2) ) to its IC(50) values was much higher than the cut-off value 10, proposed from the International Transporter Consortium (ITC) and the Food and Drug Administration (FDA). In contrast, aripiprazole and dehydroaripiprazole showed almost no inhibitory effect against the activity of human MRP4. These findings indicate that aripiprazole is unlikely to cause drug-drug interactions (DDIs) at the BBB when co-administered with substrate drugs of these drug transporters investigated. However, interactions at the intestinal absorption process may be of concern. Copyright © 2012 John Wiley & Sons, Ltd. [PubMed Citation] [Order full text from Infotrieve]

2) Chen X, Sassano MF, Zheng L, Setola V, Chen M, Bai X, Frye SV, Wetsel WC, Roth BL, Jin J
Structure-Functional Selectivity Relationship Studies of β-arrestin-biased Dopamine D(2) Receptor Agonists.
J Med Chem. 2012 Jul 30;
Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and non-canonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side-effects of drugs. However, few such ligands have been created and very little purposeful attention has been devoted to studying what we term: 'structure-functional selectivity relationships' (SFSR). We recently disclosed the first ?-arrestin-biased dopamine D(2) receptor (D(2)R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these ?-arrestin-biased D(2)R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered. [PubMed Citation] [Order full text from Infotrieve]

3) Macedo LR, Marino J, Bradshaw B, Henry J
Graves' Hyperthyroidism-Induced Psychosis Treated With Aripiprazole--A Case Report.
J Pharm Pract. 2012 Jul 25;
Graves' disease is an autoimmune syndrome with symptoms such as tachycardia, atrial fibrillation, and psychiatric symptoms. Limited evidence exists for the treatment of Graves' hyperthyroidism-induced psychosis with atypical antipsychotics. A 47-year-old female with a psychiatric history of bipolar disorder presented for the first time to the psychiatric hospital. She was agitated and grossly psychotic with delusions. Electrocardiogram showed atrial fibrillation and tachycardia. Drug screen urinalysis was negative. Endocrine workup resulted in a diagnosis of Graves' disease (thyroid-stimulating hormone [TSH]: 0.005 ?IU/mL, triiodothyronine [T3]: 537 ng/dL, thyroxine [T4]: 24 mcg/dL, free T4: 4.5 ng/dL, positive antithyroid peroxidase antibody, and antinuclear antibody). Aripiprazole 10 mg daily was initiated and titrated to 15 mg daily on day 4. On day 16, her suspicious behavior, judgment, and insight improved. Other medications given included aspirin 325 mg daily, metoprolol 25 mg twice daily, titrated to 12.5 mg twice daily, and methimazole 30 mg daily, titrated to 20 mg twice daily, and discontinued on day 29. The patient received radioiodine I-131 treatment 1 week later. We report the first known case on the use of aripriprazole to treat Graves' hyperthyroidism-induced psychosis. Further studies examining the long-term effects and appropriate dose and duration of aripiprazole in this patient population are needed. [PubMed Citation] [Order full text from Infotrieve]

4) Goikolea JM, Colom F, Capapey J, Torres I, Valenti M, Grande I, Undurraga J, Vieta E
Faster onset of antimanic action with haloperidol compared to second-generation antipsychotics. A meta-analysis of randomized clinical trials in acute mania.
Eur Neuropsychopharmacol. 2012 Jul 26;
Background: there is a lack of scientific data regarding speed of action of antimanic treatments, a relevant issue in clinical practice. Objective: to assess differences in the speed of onset of antimanic efficacy between haloperidol (as most studied first-generation antipsychotic) and second-generation antipsychotics. Experimental procedures: meta-analysis of double-blind randomized clinical trials in acute mania, comparing treatment with haloperidol and with second-generation antipsychotics. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011). Differences in mania scale score reduction at week 1 were assessed. Results: 8 randomized clinical trials fulfilled inclusion criteria and 1 of them was excluded due to low methodological quality. 2037 Manic patients had been treated with antipsychotics in the 7 trials. Haloperidol was found to be significantly more efficacious in the reduction of the mania scale score at week 1. The effect size was small, the Standardized Mean Difference (SMD) being 0.17, with a 95% Confidence Interval ranging from 0.01 to 0.32. Haloperidol was significantly more efficacious than olanzapine (SMD: 0.40 [0.21, 0.59]) and ziprasidone (0.39 [0.18, 0.61]). A non-significant trend towards superiority of haloperidol was found over aripiprazole (SMD: 0.13 [-0.02, 0.19]). There were no significant differences between haloperidol and quetiapine (0.17 [-0.11, 0.44]), and haloperidol and risperidone (SMD: -0.10 [0.30, 0.09]). Conclusions: haloperidol shows a faster onset of antimanic action than second-generation antipsychotics. This difference may be related to D2 affinity. Haloperidol may be considered a treatment option in severely ill manic patients who require urgent relief of symptoms. [PubMed Citation] [Order full text from Infotrieve]

5) Oulis P, Konstantakopoulos G, Nathanailidis E, Tsiamoura M, Kollias K
Low-dose aripiprazole in the treatment of selective serotonin reuptake inhibitors-induced orofacial and buccal dystonia.
Psychiatry Clin Neurosci. 2012 Aug;66(5):462-3.
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6) García-Ruiz AJ, Pérez-Costillas L, Montesinos AC, Alcalde J, Oyagüez I, Casado MA
Cost-effectiveness analysis of antipsychotics in reducing schizophrenia relapses.
Health Econ Rev. 2012;2(1):8.
[PubMed Citation] [Order full text from Infotrieve]

7) Huang YS, Yeh CB, Tang CS, Chen CK, Chou WJ, Chou MC, Wu YY, Liang SY, Wang LJ
Effectiveness of aripiprazole in adolescents and young adults with schizophrenia spectrum disorders: comparison of first-episode to recurrent psychosis.
Early Interv Psychiatry. 2012 Jul 22;
AIMS: The study aims to determine the clinical outcomes of aripiprazole treatment in adolescents and young adults with schizophrenia spectrum disorders. METHODS: This was a 24-week, observational, prospective study. Patients with schizophrenia spectrum disorders were prescribed a daily dose of 5?mg to 30?mg of aripiprazole. Effectiveness was assessed by the change from baseline in psychotic symptoms and quality of life. RESULTS: Forty-two patients with a mean age of 18.1?±?3.7?years were recruited. Eighteen were experiencing the first episode of psychosis (FEP), whereas the remaining 24 were non-FEP. Psychotic symptoms, but not quality of life, improved globally from baseline scores by the endpoint of the study (effect size?=?0.44). Compared with non-FEP patients, FEP patients had greater improvements (effect size?=?0.45) in some clinical outcome dimensions during the 24-week aripiprazole treatment. CONCLUSION: We observed significant improvements of medium effect sizes in psychotic symptoms of patients with schizophrenia spectrum disorders within a naturalistic clinical setting, especially for FEP patients. [PubMed Citation] [Order full text from Infotrieve]

8) Yoshimura R, Kishi T, Hori H, Ikenouchi-Sugita A, Katsuki A, Umene-Nakano W, Iwata N, Nakamura J
Comparison of the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depressive disorder.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jul 17;
OBJECTIVE: Only two-thirds of depressive patients respond to antidepressant treatment. In recent years, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we compared the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depression. SUBJECTS AND METHODS: Twenty-four patients who met the DSM-IV criteria for major depressive disorder who did not at least two different classes of antidepressants were enrolled in the study. Nine were male and thirteen were female, and their ages ranged from 28 to 66 (mean±SD=39±12) years. Patients were prescribed paroxetine (n=11) or sertraline (n=13) for 4weeks. Then, those whose scores on the 17-item Hamilton Rating Scale for Depression (HAMD17) decreased below 50% received adjunctive therapy of aripiprazole for 4weeks. RESULTS: Although the use of either combination treatment decreased the HAMD17 scores compared to the respective monotherapy, there was no significant difference in HAMD17 scores between the paroxetine plus aripiprazole group and sertraline plus aripiprazole group. CONCLUSION: Aripiprazole augmentation therapy with paroxetine or sertraline was equally effective and tolerated in patients with refractory major depressive order. [PubMed Citation] [Order full text from Infotrieve]

9) Wisniewski CS, Robert S
Strategies for transitioning therapy to aripiprazole from other antipsychotics in schizophrenia.
Ann Pharmacother. 2012 Jul;46(7-8):1097-104.
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10) Dratcu L, Bobmanuel S, Davies W, Farmer A, George M, Rana T, Singh M, Turner M
A UK panel consensus on the initiation of aripiprazole for the treatment of bipolar mania.
Int J Psychiatry Clin Pract. 2012 Jul 19;
Abstract Objective: The objective of this consensus paper is to provide practical guidance on why and how aripiprazole, with its distinct pharmacological and side effect profile, should be used for treatment of acute bipolar mania. Methods: An advisory panel of UK healthcare professionals, with extensive experience of prescribing aripiprazole for acute bipolar mania, met to discuss its use in this setting. Results: The panel agreed that aripiprazole is effective in treating bipolar mania when prescribed and dosed appropriately, in both the short and long term, as monotherapy or in combination with a mood stabiliser. Unlike other atypical agents, aripiprazole has antimanic effects that are not associated with sedation, which is beneficial for patients, particularly in the long term. If rapid tranquillisation is required when initiating aripiprazole in acutely disturbed patients, short-term co-prescription of a benzodiazepine is recommended. Most side effects associated with aripiprazole occur within the first 1-3 weeks and are usually transient and easily treatable. Aripiprazole poses low risk of metabolic side effects, sexual dysfunction and anhedonia, which can facilitate treatment adherence and help improve clinical outcomes. Conclusions: Aripiprazole can be safely and effectively used as a first-line treatment for acute bipolar mania. [PubMed Citation] [Order full text from Infotrieve]

11) Maher AR, Theodore G
Summary of the comparative effectiveness review on off-label use of atypical antipsychotics.
J Manag Care Pharm. 2012 Jun;18(5 Suppl B):1-20.
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12) Kalsekar I, Wagner JS, Dibonaventura M, Bates J, Forbes R, Hebden T
Comparison of health-related quality of life among patients using atypical antipsychotics for treatment of depression: results from the National Health and Wellness Survey.
Health Qual Life Outcomes. 2012 Jul 17;10(1):81.
ABSTRACT: BACKGROUND: Use of atypical antipsychotics (AA) in combination with an antidepressant is recommendedas an augmentation strategy for patients with depression. However, there is a paucity of datacomparing aripiprazole and other AAs in terms of patient reported outcomes. Therefore, theobjective of this study was to examine the levels of HRQoL and health utility scores inpatients with depression using aripiprazole compared with patients using olanzapine,quetiapine, risperidone and ziprasidone. METHODS: Data were obtained from the 2009, 2010, and 2011 National Health and Wellness Survey(NHWS), a cross-sectional, internet-based survey that is representative of the adult USpopulation. Only those patients who reported being diagnosed with depression and taking anantidepressant and an atypical antipsychotic for depression were included. Patients taking anatypical antipsychotic for less than 2 months or who reported being diagnosed with bipolardisorder or schizophrenia were excluded. Patients taking aripiprazole were compared withpatients taking other atypical antipsychotics. Health-related quality of life (HRQoL) andhealth utilities were assessed using the Short Form 12-item (SF-12) health survey.Differences between groups were analyzed using General Linear Models (GLM) controllingfor demographic and health characteristics. RESULTS: Overall sample size was 426 with 59.9% taking aripiprazole (n = 255) and 40.1% (n = 171)taking another atypical antipsychotic (olanzapine (n = 19), quetiapine (n = 127), risperidone(n = 14) or ziprasidone (n = 11)). Of the SF-12 domains, mean mental component summary(MCS) score (p = .018), bodily pain (p = .047), general health (p = .009) and emotional rolelimitations (p = .009) were found to be significantly higher in aripiprazole users indicatingbetter HRQoL compared to other atypical antipsychotics. After controlling for demographicand health characteristics, patients taking aripiprazole reported significantly higher meanmental SF-12 component summary (34.10 vs. 31.43, p = .018), bodily pain (55.19 vs. 49.05,p = .047), general health (50.05 vs. 43.07, p = .009), emotional role limitations (49.44 vs.41.83, p = .009), and SF-6D utility scores (0.59 vs. 0.56, p = .042). CONCLUSIONS: Comparison of patients taking aripiprazole with a cohort of patients using another AA fordepression demonstrated that aripiprazole was independently associated with better (bothstatistically and clinically) HRQoL and health utilities. [PubMed Citation] [Order full text from Infotrieve]

13) Xiang YT, Kreyenbuhl J, Dickerson FB, Ungvari GS, Wang CY, Si TM, Lee EH, He YL, Chiu HF, Yang SY, Chong MY, Tan CH, Kua EH, Fujii S, Sim K, Yong MK, Trivedi JK, Chung EK, Udomratn P, Chee KY, Sartorius N, Shinfuku N
Use of first- and second-generation antipsychotic medications in older patients with schizophrenia in Asia (2001-2009).
Aust N Z J Psychiatry. 2012 Jul 11;
Objective:This study examined the prescribing patterns of several first- (FGAs) and second-generation antipsychotic (SGAs) medications administered to older Asian patients with schizophrenia during the period between 2001 and 2009.Method:Information on hospitalized patients with schizophrenia aged 65 or older was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study (2001-2009). There were no older patients in Thailand, therefore data on 467 patients in eight Asian countries and territories including China, Hong Kong SAR, India, Japan, Korea, Malaysia, Singapore, and Taiwan were analysed. Cross-sectional socio-demographic data, clinical characteristics and antipsychotic prescriptions were assessed using a standardized protocol and data collection procedure.Results:Of the 467 patients, 192 patients (41.1%) received FGAs only, 166 (35.5%) received SGAs only and 109 (23.3%) received a combination of FGAs and SGAs. Of the FGAs, haloperidol was the most commonly used (31.3%; mean 9.4 ± 6.7 mg/day), followed by chlorpromazine (15.4%; mean 126.4 ± 156.4 mg/day) and sulpiride (6.6%; mean 375.0 ± 287.0 mg/day). Of the SGAs, risperidone was the most commonly used (31.5%; mean 4.5 ± 2.7 mg/day), followed by olanzapine (13.1%; mean 13.6 ± 6.5 mg/day), quetiapine (7.3%; mean 325.0 ± 237.3 mg/day) and aripiprazole (1.9%; mean 17.6 ± 7.7 mg/day).Conclusions:FGAs and higher doses of certain SGAs (risperidone, olanzapine and quetiapine) were still commonly dispensed to older Asian patients with schizophrenia. Considering older patients' reduced tolerability of potentially severe side effects associated with FGAs and higher doses of certain SGAs, continuing education and training addressing the rational use of antipsychotics in this population is clearly needed. [PubMed Citation] [Order full text from Infotrieve]

14) Martens MA, Seyfer DL, Andridge RR, Foster JE, Chowdhury M, McClure KE, Coury DL
Parent report of antidepressant, anxiolytic, and antipsychotic medication use in individuals with Williams syndrome: Effectiveness and adverse effects.
Res Dev Disabil. 2012 Jul 7;33(6):2106-2121.
Williams syndrome (WS) is a neurodevelopmental genetic disorder characterized in part by anxiety and behavioral difficulties. We examine the effectiveness and adverse effects of antidepressant, anxiolytic, and antipsychotic medications in individuals with WS. A total of 513 parents/caregivers completed a survey of psychotropic medication usage regarding their child or adult with WS. Twenty-four percent (24%) of the individuals had been prescribed an SSRI medication, while 12% had been prescribed another type of antidepressant or anxiolytic. Overall, 81% of respondents indicated that SSRI medications were either "Helpful" or "Somewhat Helpful", with paroxetine reported to be the least helpful. Sixty-four percent (64%) of survey participants reported that non-SSRI antidepressants and anxiolytics were either "Helpful" or "Somewhat Helpful" in treating symptoms of anxiety. Side effects for the antidepressants and anxiolytics were typically neurological in nature. Ten percent (10%) of the survey participants reported taking an antipsychotic medication, with risperidone and quetiapine described as more helpful than aripiprazole. Medication effectiveness may be related to the impact on serotonin levels. These findings call for further studies of medication usage in WS in order to improve their quality of life. [PubMed Citation] [Order full text from Infotrieve]

15) Ghanizadeh A
Systemic review of aripiprazole for the treatment of children and adolescents with tic disorders.
Neurosciences (Riyadh). 2012 Jul;17(3):200-4.
This study aimed to systematically review the data related to the treatment of tic disorders through aripiprazole administration, an atypical antipsychotic. The databases of MEDLINE/PubMed and Google Scholar were searched using the key words: "aripiprazole," "tic," and "Tourette," and the relevant titles retrieved. Thirty-five articles met the inclusion criteria and were further scrutinized. Most of the articles were case reports, and only 2 published trials included control groups. The number of randomized double-blind controlled clinical trials was zero, therefore, no strong evidence, provided by one, or more well-designed randomized controlled clinical trials, was found. Current evidence suggests that aripiprazole is effective for treating tic and Tourette disorders in both children and adolescents. Moreover, it seems that its adverse effect profile is safer than pimozide and some other antipsychotics. Therefore, double-blind randomized placebo-controlled studies are needed to provide strong evidence on the issue. [PubMed Citation] [Order full text from Infotrieve]

16) Magaudda A, Imbesi D, Di Rosa G
Efficacy of aripiprazole in a child with involuntary emotional expression disorder.
J Neuropsychiatry Clin Neurosci. 2012 Mar 1;24(2):E5-6.
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17) Geoffroy PA, Rolland B, Guardia D, Warembourg F, Cottencin O
Use of aripiprazole in treatment of cannabis dependence in a patient presenting with borderline personality disorder.
J Neuropsychiatry Clin Neurosci. 2012 Mar 1;24(2):E37.
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18) Mizushima J, Takahata K, Kawashima N, Kato M
Successful treatment of dopamine dysregulation syndrome with dopamine D2 partial agonist antipsychotic drug.
Ann Gen Psychiatry. 2012;11(1):19.
ABSTRACT: Dopamine dysregulation syndrome (DDS) consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson's disease (PD). Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system. [PubMed Citation] [Order full text from Infotrieve]

19) Ravinder S, Bapuji AT, Mukkanti K, Raju DR, Ravikiran HL, Reddy DC
Development and Validation of an LC-ESI-MS Method for Quantitative Determination of Aripiprazole in Human Plasma and an Application to Pharmacokinetic Study.
J Chromatogr Sci. 2012 Jul 5;
A selective, sensitive, high pressure liquid chromatography-positive electrospray ionization tandem mass spectrometry method was developed and validated for the quantification of aripiprazole in human K(2)EDTA plasma using zolpidem tartrate as an internal standard. The analyte and internal standard were extracted from human plasma by solid-phase extraction using methanol. The eluted samples were chromatographed on a Grace Smart RP 18 4.6 × 100 mm, 3 µ column by using a 95:5 v/v mixture of methanol and ammonium acetate buffer (30 mM, pH 5.0 ± 0.05) as a gradient mobile phase at a flow rate of 0.6 mL/min, and analyzed by mass spectrometry in the multiple reaction monitoring mode using the [M + H](+) ions m/z 448.03 ? 285.14 for aripiprazole and m/z 308.13 ? 235.25 for the internal standard (zolpidem tartrate), respectively. Calibration plots were linear over the concentration range of 0.20 to 60.01 ng/mL. Intra-day and inter-day precision (percent coefficient of variation) and accuracy (percent nominal) for quality control samples (0.60, 30.60 and 45.59 ng/mL) ranged between 2.28 and 8.93% and between 92.50 and 107.07%, respectively. Extraction recovery of aripiprazole from plasma was in the range 75.56-79.57%; mean recovery was 77.35%. The main pharmacokinetic parameters were T(max) = (4.00 ± 2.336) C(max) = (55.16 ± 13.490) and AUC = (1846.28 ± 484.686). [PubMed Citation] [Order full text from Infotrieve]

20) Russo E, Citraro R, Davoli A, Gallelli L, Donato Di Paola E, De Sarro G
Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity.
Neuropharmacology. 2012 Jul 2;
Aripiprazole (APZ) is regarded as a first-line atypical antipsychotic used for the treatment of first and multiple episodes of schizophrenia to improve positive- and negative-symptoms. Its therapeutic indications were extended to acute manic and mixed episodes associated with bipolar disorder. In addition, APZ was approved as an adjunct therapy for major depressive disorder in 2007. Compared to other antipsychotic drugs, APZ has a unique pharmacological profile. It is a partial agonist at D(2) dopamine receptors and serotonin 5-HT(1A) and 5-HT(7) receptors, whereas it is an antagonist at serotonin 5-HT(2A) and 5-HT(6) receptors. Since epilepsy is often accompanied with neurological comorbidities such as depression, anxiety and cognitive deficits caused by both the disease and/or drug treatment, we wished to examine the effects of a sub-chronic treatment (>14 consecutive days) with APZ (0.3, 1 and 3 mg/kg; i.p.) on both absence seizures and WAG/Rij rat's behavior using different standard paradigms: Open field (OF) test, elevated plus maze (EPM) test, forced swimming (FS) test, sucrose consumption (SC) test and Morris water maze (MWM). WAG/Rij rats represent a validated genetic animal model of absence epilepsy with mild-depression comorbidity, also including other behavioral alterations. APZ treatment showed some anti-absence properties and regarding the behavioral comorbidity in this rat strain, we observed that APZ possesses clear antidepressant effects in the FS and SC tests also increasing memory/learning function in the Morris water maze test. In the two anxiety models used, APZ showed only minor effects. In conclusion, our results indicate that APZ might actually have a potential in treating absence seizures or as add-on therapy but more interestingly, these effect might be accompanied by positive modulatory actions on depression, anxiety and memory which might be also beneficial in other epileptic syndromes. This article is part of a Special Issue entitled 'Cognitive Enhancers'. [PubMed Citation] [Order full text from Infotrieve]