ABILIFY aripiprazole

Aripiprazole AbilifyAbilify is an atypical antipsychotic with proported fewer side effects than the other current anti psychotics on the market. Abilify is less likely to cause weight gain, heart disturbances, blood pressure problems etc. For some of us bipolar II individuals, Abilify appears to help big time in eliminating depression and anxiety that antidepressants could not eliminate. For some it is definitely a miracle drug. It appears to be well tolerated for bipolar youths and helps with mania.
For this individual Risperdal works better for obsessive thought and irritation, but I would rather trade getting rid of the underlying depression.(There was one small open study for OCD and Abilify)

"PRINCETON, NEW JERSEY AND TOKYO, JAPAN (March 07, 2005) -- Bristol-Myers Squibb Company (NYSE: BMY) and Otsuka Pharmaceutical Co., Ltd. today announced that the U.S. Food and Drug Administration (FDA) approved ABILIFYŽ (aripiprazole) Tablets and Oral Solution for maintaining efficacy in patients with Bipolar I Disorder with a recent manic or mixed episode who had been stabilized and then maintained for at least six weeks. The FDA approved ABILIFY for the treatment of acute bipolar mania, including manic and mixed episodes associated with bipolar disorder, on September 29, 2004.

J Affect Disord. 2005 May;86(1):99-104.: Treatment of residual anxiety symptoms with adjunctive aripiprazole in depressed patients taking selective serotonin reuptake inhibitors.
Adson DE, Kushner MG, Fahnhorst TA.
Department of Psychiatry, University of Minnesota, F282/2A West, 2450 Riverside Ave., Minneapolis, MN 55454-1495, United States.
BACKGROUND: Depression and anxiety are common disorders and have substantially overlapping symptom complexes. Not surprisingly, treatment approaches are similar for both conditions with the selective serotonin reuptake inhibitors (SSRIs) as the initial therapy of choice. However, after first line treatments have been deployed, residual symptoms are often problematic. Augmentation strategies to address these difficulties are an area of active investigation. This study assessed aripiprazole as adjunctive therapy to SSRIs for patients with persistent anxiety symptoms complicating a depression or anxiety disorder. METHODS: Ten patients who had been receiving SSRIs for at least 6 weeks, but still had clinically significant anxiety symptoms, were enrolled in an open label, flexibly-dosed study of adjunctive aripiprazole. Clinical status was assessed with the Hamilton Anxiety Rating Scale (HAM-A), Montgomery Asberg Rating Scale (MADRS), and Sheehan Disability Scale (SDS). RESULTS: Eighty percent of the subjects had a greater than 50% reduction of symptoms on these outcome measures by week 2 of therapy, and continued with further decrements in symptoms throughout the course of the study. CONCLUSIONS: The results of this trial provide preliminary evidence that aripiprazole may be an effective adjunctive treatment in individuals on SSRIs with residual symptoms of anxiety or depression. More rigorous double-blind studies are warranted to confirm and elucidate the potential role of aripiprazole in these conditions.

CNS Spectr. 2005 Feb;10(2):141-8. : Aripiprazole in the treatment of pediatric bipolar disorder: a systematic chart review.
Biederman J, McDonnell MA, Wozniak J, Spencer T, Aleardi M, Falzone R, Mick E.
Pediatric Psychopharmacology Research Office, Massachusetts General Hospital, Boston, MA 02114, USA.
jbiederman@partners.org
BACKGROUND: Pediatric bipolar disorder is a serious neuropsychiatric disorder associated with high levels of morbidity and disability. OBJECTIVE: This is a systematic chart review of all outpatient youth with the diagnosis of bipolar disorder and bipolar spectrum disorder treated with aripiprazole either alone or as add-on to ongoing treatments. METHOD: Medical records were reviewed to identify all subjects with bipolar and bipolar spectrum disorder prescribed aripiprazole in our clinic. During the chart review, the Clinical Global Impression scale was completed by the treating clinicians to determine usefulness. RESULTS: Forty-one youths (mean age+/-SD: 11.4+/-3.5 years) with bipolar spectrum disorder who had been treated with aripiprazole were identified. These children received a mean daily dose of aripiprazole 16.0+/-7.9 mg over an average of 4.6 months. Using a Clinical Global Impression-Improvement scale score of <2 (very much/much improved) to define robust improvement, 71% showed improvement in manic symptoms. Treatment with aripiprazole was well tolerated. CONCLUSION: This study suggests that aripiprazole may be a useful and well-tolerated treatment for youth with bipolar disorder and it supports the need for controlled clinical trials of this compound in juvenile mania. "

: Int Clin Psychopharmacol. 2005 Jan;20(1):9-11. : Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients.
Worthington JJ 3rd, Kinrys G, Wygant LE, Pollack MH.
Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital, Boston, Massachusetts, USA
More than half of anxiety and depression patients treated with an adequate course of antidepressants fail to fully improve. We retrospectively examined whether treatment-resistant depression and anxiety disorder patients responded to and tolerated augmentation with the atypical antipsychotic, aripiprazole. We report on patients with depression and anxiety disorders, including panic disorder, generalized anxiety disorder, social anxiety and post-traumatic stress disorder, who had an incomplete response to a variety of selective serotonin reuptake inhibitors (SSRIs) and who received augmentation with aripiprazole. The primary outcome measure was the Clinical Global Impression of Improvement (CGI-I). In the intent-to-treat analysis, the mean+/-SD CGI-S was 3.8+/-1.3 at endpoint. Fifty-nine percent of subjects received CGI-I ratings of 1 or 2, 'much improved' or 'very much improved,' in terms of their depression and anxiety symptoms at the end of 12 weeks. Several patients showed an early (weeks 1-5), as well as sustained, response to augmentation with doses of aripiprazole between 15 and 30 mg/day. The results suggest that aripiprazole may be effective as an augmentation for patients with persistent depressive and anxiety disorders despite initial SSRI treatment. Because this is a retrospective case review, further prospective studies are required to confirm these findings

J Clin Pharmacol. 2005 Jan;45(1):89-93. : Pharmacokinetics of aripiprazole and concomitant lithium and valproate.
Citrome L, Josiassen R, Bark N, Salazar DE, Mallikaarjun S.
Nathan S. Kline Institute for Psychiatic Research and the Rockland Psychiatric Center, Orangeburg, NY 10962, USA.
The objective of this study was to assess the pharmacokinetics of the antipsychotic aripiprazole when coadministered with lithium or valproate. Two open-label, sequential treatment design studies were conducted in chronically institutionalized patients with schizophrenia or schizoaffective disorder requiring treatment with lithium (n = 12) or valproate (divalproex sodium) (n = 10). Patients received aripiprazole 30 mg/day on days 1 to 14 and aripiprazole with concomitant therapy on days 15 to 36. Lithium was titrated from 900 mg until serum concentrations reached 1.0 to 1.4 mEq/L for at least 5 days. Valproate was titrated to 50 to 125 mg/L. Coadministration with lithium increased mean Cmax and AUC values of aripiprazole by about 19% and 15%, respectively, whereas the apparent oral clearance decreased by 15%. There was no effect on the steady-state pharmacokinetics of the active metabolite of aripiprazole. Coadministration with valproate decreased the AUC and Cmax of aripiprazole by 24% and 26%, respectively, with minimal effects on the active metabolite. Therapeutic doses of lithium and divalproex had no clinically significant effects on the pharmacokinetics of aripiprazole in patients with schizophrenia or schizoaffective disorder.

J Clin Psychiatry. 2005 Jan;66(1):49-51.: The use of aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients.
Connor KM, Payne VM, Gadde KM, Zhang W, Davidson JR.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
kathryn.connor@duke.edu
OBJECTIVE: To assess the effectiveness of aripiprazole, an atypical antipsychotic with dopamine- and serotonin-stabilizing properties, as monotherapy in treating obsessive-compulsive disorder (OCD). METHOD: Adult subjects meeting DSM-IV criteria for OCD who were not currently receiving pharmacotherapy for the disorder were entered into an 8-week open-label trial of treatment with aripiprazole (10-30 mg/day). Efficacy assessments included the Yale-Brown Obsessive Compulsive Scale (YBOCS) and the Clinical Global Impressions-Improvement scale. Safety assessments included evaluation of vital signs, weight, and treatment-emergent side effects. Data were collected from June 2003 to August 2004. RESULTS: Eight subjects were enrolled, 7 of whom took at least 1 dose of study medication. Using the last observation carried forward, the mean total YBOCS score decreased from 23.9 at baseline to 17.6 at the final visit (p = .06). More pronounced improvement was observed in compulsive symptoms (p < .05) compared with obsessive symptoms (p = .09). Three subjects (43%) responded to treatment, showing a 30% or greater reduction in YBOCS total score. Two subjects discontinued treatment within 1 week due to side effects (akathisia, nausea). While no changes were noted in vital signs, a mean weight gain of 1.8 kg was observed. CONCLUSION: Although from a small, open-label study, these results suggest that aripiprazole holds promise for treating OCD. Larger, controlled studies of aripiprazole as monotherapy and as augmentation in partial responders to selective serotonin reuptake inhibitors are needed.

Schizophr Res. 2004 Sep 1;70(1):1-17. : The effects of antipsychotic therapy on serum lipids: a comprehensive review.
Meyer JM, Koro CE.
University of California, San Diego VAMC (MC 116A), 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Objectives: The purpose of this paper is to review the literature since 1970 documenting the effects of antipsychotic agents on serum lipids, including a discussion of possible mechanisms for the observed phenomena, the clinical significance and recommendations for monitoring hyperlipidemia during antipsychotic therapy. Results: High-potency conventional antipsychotics (e.g., haloperidol) and the atypical antipsychotics, ziprasidone, risperidone and aripiprazole, appear to be associated with lower risk of hyperlipidemia. Low-potency conventional antipsychotics (e.g., chlorpormazine, thioridazine) and the atypical antipsychotics, quetiapine, olanzapine and clozapine, are associated with higher risk of hyperlipidemia. Possible hypotheses for lipid dysregulation include weight gain, dietary changes and the development of glucose intolerance. Conclusions: Given the multiple cardiovascular risk factors seen in patients with schizophrenia, great care must be exercised in the choice of antipsychotic therapy to minimize the medical burden of additional risk imposed by hyperlipidemia. It is recommended that a lipid panel be obtained at baseline in all patients with schizophrenia, annually thereafter for patients on agents associated with lower risk of hyperlipidemia and quarterly in patients on agents associated with higher risk for hyperlipidemia. All patients with persistent dyslipidemia should be referred for lipid-lowering therapy or switched to a less lipid-offending antipsychotic agent.

online discount pharmacy for cheap medications

Pharmacotherapy. 2004 Feb;24(2):212-28. : Aripiprazole, a novel atypical antipsychotic drug.
Argo TR, Carnahan RM, Perry PJ.
College of Pharmacy, University of Iowa, Iowa City, Iowa 52242-1112, USA.
Before the 1990s, treatment of psychoses centered on conventional agents whose tolerability was limited by extrapyramidal side effects (EPS). The past decade has seen the emergence of a newer generation of antipsychotic agents, first with clozapine and followed shortly by risperidone, olanzapine, quetiapine, and ziprasidone. These agents have been touted as providing better negative symptom efficacy, less impaired cognition, and lower risk of extrapyramidal syndromes. However, evolving evidence suggests that several drugs in this class may be associated with significant weight gain and lipid abnormalities. Aripiprazole, a new atypical antipsychotic drug, displayed efficacy similar to that of haloperidol and risperidone and superior to that of placebo in numerous clinical trials. Aripiprazole does not cause significant prolactin elevation and is associated with a low rate of clinically significant weight gain compared with other atypical antipsychotics. Patients receiving aripiprazole experienced EPS at a rate similar to that seen with placebo. Aripiprazole provides a new treatment option with limited adverse effects for patients in need of antipsychotic therapy.

Paediatr Drugs. 2004;6(1):33-44. : Weight gain associated with atypical antipsychotic use in children and adolescents: prevalence, clinical relevance, and management.
Stigler KA, Potenza MN, Posey DJ, McDougle CJ.
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202-4800, USA.
Atypical antipsychotics are increasingly prescribed to children and adolescents with neuropsychiatric disorders. Although their profile of potent antagonism at specific serotonin and dopamine receptors offers certain advantages compared with typical antipsychotics, their use has been associated with various adverse effects, including significant weight gain. This adverse effect is of particular concern in children and adolescents, secondary to the immediate and long-term health risks associated with weight gain, including obesity, diabetes mellitus, and hyperlipidemia. Indeed, from 1963 to 1991, the prevalence of obesity has approximately doubled in youth. Prior to selecting an atypical antipsychotic, a detailed review of the predictors of weight gain is necessary for every child and adolescent. Published data suggest that clozapine and olanzapine are associated with considerable weight gain, whereas risperidone and quetiapine have a moderate risk. Alternatively, ziprasidone and aripiprazole may exhibit a low risk for this adverse effect. Whereas behavioral and pharmacologic measures are available to manage weight gain associated with atypical antipsychotics, research is needed to establish more effective and safe interventions for this adverse effect in children and adolescents

Am J Health Syst Pharm. 2003 Dec 1;60(23):2437-45. : Aripiprazole.
Winans E.
Departments of Pharmacy Practice and Psychiatry, University of Illinois at Chicago, USA.
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.(

Eur J Pharmacol. 2004 Jun 16;493(1-3):75-83.: Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain.
Li Z, Ichikawa J, Dai J, Meltzer HY.
Division of Psychopharmacology, Departments of Psychiatry and Pharmacology, Vanderbilt University School of Medicine, USA.
Aripiprazole,7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy}-3,4-dihydro-carbostycil (OPC-14597), a novel atypical antipsychotic drug, is a dopamine D2 receptor partial agonist with functional 5-HT(2A) receptor antagonist, and 5-HT(1A) receptor partial agonist properties as well. Other atypical antipsychotic drugs, e.g. clozapine, but not typical antipsychotic drugs, e.g. haloperidol, produce significant increases in dopamine and acetylcholine release in the medial prefrontal cortex in rats, effects believed to be related to the ability to improve cognitive function. The increase in the medial prefrontal cortex dopamine release by the atypical antipsychotic drugs has been shown to be partially inhibited by N-[2[4-)2-methoxyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635), a selective 5-HT(1A) receptor antagonist. Aripiprazole, 0.1 and 0.3 mg/kg, significantly increased dopamine release in the hippocampus. Moreover, aripiprazole, 0.3 mg/kg, slightly but significantly increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. These increases were significantly inhibited by WAY100635. By contrast, aripiprazole, 3.0 mg/kg and 10 mg/kg, significantly decreased dopamine release in the nucleus accumbens but not the medical prefrontal cortex. However, aripiprazole 10 mg/kg significantly decreased dopamine release in the both regions. Aripiprazole had no effect on acetylcholine release in the medial prefrontal cortex, hippocampus, or nucleus accumbens at any dose, except for 3.0 mg/kg, which decreased acetylcholine release in the nucleus accumbens only. Aripiprazole, 0.3 mg/kg, transiently potentiated haloperidol (0.1 mg/kg)-induced dopamine release in the medial prefrontal cortex but inhibited that in the nucleus accumbens. The present study demonstrated that aripiprazole, at low doses of 0.1 and 0.3 mg/kg, increases dopamine release in the medial prefrontal cortex and hippocampus. It also suggests that the function of both the medial prefrontal cortex and hippocampus may contribute to the ability of aripiprazole to improve negative symptom and cognition.

CNS Drugs. 2004;18(4):251-67. : Dopamine partial agonists: a new class of antipsychotic.
Lieberman JA.
University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7160, USA.
jlieberman@unc.edu
This review examines the development of dopamine partial agonists as a new class of antipsychotic agents. Partial agonists have a lower intrinsic activity at receptors than full agonists, allowing them to act either as a functional agonist or a functional antagonist, depending on the surrounding levels of naturally occurring neurotransmitter (full agonist). In the absence of a full agonist, partial agonists show functional agonist activity, binding to the receptor to produce a response. In the presence of a full agonist, partial agonists show functional antagonist activity, as receptor binding reduces the response from that seen with the full agonist. A partial agonist at dopamine D(2) receptors therefore offers an attractive option for the treatment of schizophrenia. It should act as a functional antagonist in the mesolimbic dopamine pathway, where excessive dopamine activity is thought to cause positive symptoms, but show functional agonist activity in the mesocortical pathway, where reduced dopamine activity is thought to be associated with negative symptoms and cognitive impairment. In addition, it should avoid the complete blockade of the nigrostriatal or tuberoinfundibular pathways, associated with extrapyramidal symptoms (EPS) and elevated prolactin levels, respectively. Clinical trials with aripiprazole - a new antipsychotic, which shows partial agonist activity at D(2) receptors and serotonin 5-HT(1A) receptors, and antagonist activity 5-HT(2A) receptors - have demonstrated the value of this treatment approach. Aripiprazole produced significant improvements in positive and negative symptoms in short- and long-term studies of patients with schizophrenia or schizoaffective disorder. Improvements occurred rapidly after the start of treatment, and were sustained throughout studies lasting up to 52 weeks. Significantly more patients responded to aripiprazole treatment than to haloperidol in the 52-week study, and aripiprazole-treated patients showed significantly greater improvements in negative and depressive symptoms than those receiving haloperidol. Aripiprazole treatment was well tolerated in both short- and long-term studies, showing a low liability for EPS and hyperprolactinemia, a lack of QTc prolongation, and minimal weight gain or sedation. In conclusion, the findings from clinical studies of aripiprazole show that dopamine partial agonists offer a novel, effective and well-tolerated treatment approach for patients with schizophrenia.

: Curr Med Res Opin. 2004;20(2):207-13. : Focus on aripiprazole.
Green B.
Cheadle Royal Hospital, and Honorary Senior Lecturer, University of Liverpool, UK.
drbengreen@hotmail.com
This paper is an overview of recently published research concerning the neuroleptic drug aripiprazole. Aripiprazole is an antipsychotic drug with high affinity for D(2)- and D(3)-receptors and the dopamine autoreceptor. It also has serotonin 5-HT(1A)-receptor partial agonist and 5-HT(2A)-receptor antagonist properties. It is prescribed in the treatment of schizophrenia and is under the treatment of schizophrenia and schizoaffective investigation for treatment of bipolar disorder. The drug is given by mouth in an initial dose of 10 or 15 mg once daily. The dose may be adjusted at intervals of not less than 2 weeks up to a maximum of 30 mg daily. It appears to be useful in disorder and has a better side-effect profile than haloperidol

Int Clin Psychopharmacol. 2004 Jan;19(1):45-8. : Aripiprazole possibly worsens psychosis.
Ramaswamy S, Vijay D, William M, Sattar SP, Praveen F, Petty F.
Creighton University/University of Nebraska Psychiatry Residency Program, 3528 Dodge Street Omaha, NE 68131, USA.
sriramrr@rocketmail.com
Aripirazole is a novel antipsychotic that functions as a partial agonist at the dopamine D2 receptor and, thus, might theoretically worsen psychosis. We report a series of four clinical cases of exacerbation of psychosis related to initiation of aripiprazole therapy. Cases 1 and 2 demonstrated the worsening of psychosis following initiation of aripiprazole (15-30 mg daily) while tapering off the previous atypical antipsychotic. Cases 3 and 4 demonstrated worsening of psychosis following the addition of aripiprazole (15-30 mg daily) to an atypical antipsychotic. In two out of the four cases, discontinuation of arpiprazole resulted in improvement of psychotic symptoms. Although the cases presented are suggestive of a relationship between initiation of aripiprazole therapy and worsening of psychosis, further research is needed to clarify any potential association

Neuropsychopharmacology. 2003 Dec;28(12):2064-76. : SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.
Claustre Y, Peretti DD, Brun P, Gueudet C, Allouard N, Alonso R, Lourdelet J, Oblin A, Damoiseau G, Francon D, Suaud-Chagny MF, Steinberg R, Sevrin M, Schoemaker H, George P, Soubrie P, Scatton B.
Sanofi-Synthelabo Recherche, Discovery Research, Bagneux, France.
Yves.Claustre@Sanofi-Synthelabo.com
SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.

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Int J Neuropsychopharmacol. 2003 Dec;6(4):325-37. : Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia.
Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, Archibald D, Ingenito G, Marcus R, Pigott T.
Department of General Psychiatry, University of Vienna, Vienna, Austria.
sk@akih-wien.ac.at
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.

1: Arch Gen Psychiatry. 2003 Oct;60(10):974-7. : Mechanism of new antipsychotic medications: occupancy is not just antagonism.
Grunder G, Carlsson A, Wong DF.
Department of Psychiatry, University of Mainz, Mainz, Germany.
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

Am J Psychiatry. 2003 Sep;160(9):1651-8. : A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania.
Keck PE Jr, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G; Aripiprazole Study Group.
Biological Psychiatry Program, Department of Psychiatry, University of Cincinnati College of Medicine, PO Box 670559, Cincinnati, OH 45267-0559, USA.
paul.keck@uc.edu

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.

Curr Psychiatry Rep. 2003 Aug;5(4):320-6. : Treatment for mood and anxiety disorders: quetiapine and aripiprazole.
Sajatovic M.
Department of Psychiatry, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
martha.sajatovic@uhhs.com
Atypical antipsychotic agents have a broad range of therapeutic efficacy, a relatively low incidence of causing extrapyramidal adverse effects, and a low tardive dyskinesia profile. This has led to very rapid growth in the use of these compounds as broad-spectrum psychotropic agents, and it has been reported that more than 70% of prescriptions for atypical antipsychotic medications are being used for conditions other than schizophrenia. In the area of bipolar disorder, in particular, atypical antipsychotic agents appear to positively affect illness outcome, and are considered potential first-line treatment agents. Quetiapine was approved by the US Food and Drug Administration in 1997, and is currently marketed in the US to treat schizophrenia. Aripiprazole was recently approved for the treatment of schizophrenia by the US Food and Drug Administration in late 2002, and is being used increasingly in clinical settings. Recent reports suggest that quetiapine and aripiprazole are valuable additions to the psychotropic armamentarium for the treatment of mood and anxiety disorders. Data from clinical trials and clinical reports are discussed herewith.

Neuropsychopharmacology. 2003 Aug;28(8):1400-11. Epub 2003 May 21. : Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R.
Department of Biochemistry, Case Western Reserve University Medical School, 10900 Euclid Avenue, Cleveland, OH 44106-4935, USA.

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)).

Arch Gen Psychiatry. 2003 Jul;60(7):681-90. : Aripiprazole, an Antipsychotic With a Novel Mechanism of Action, and Risperidone vs Placebo in Patients With Schizophrenia and Schizoaffective Disorder.
Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, Stringfellow J, Ingenito G, Marder SR.
Brain Imaging Center, University of California, Irvine, 92697, USA.
sgpotkin@uci.edu
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.

Schizophr Res. 2003 Jun 1;61(2-3):123-36. : Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials.
Marder SR, McQuade RD, Stock E, Kaplita S, Marcus R, Safferman AZ, Saha A, Ali M, Iwamoto T.
Department of Psychiatry, David Geffen School of Medicine at UCLA, 760 Westwood Plaza, 90024, Los Angeles, CA, USA.
marder@ucla.edu
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

Ann Pharmacother. 2003 May;37(5):687-94. : Aripiprazole: a new atypical antipsychotic drug.
Bowles TM, Levin GM.
Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville, FL, USA.
OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of aripiprazole for the treatment of schizophrenia. DATA SOURCES: Information was selected from MEDLINE (1995-August 2002). Abstracts, scientific posters, and presentations were also used. STUDY SELECTION/DATA EXTRACTION: All published information regarding the pharmacokinetic, pharmacodynamic, and clinical characteristics of aripiprazole was considered. Studies providing a comprehensive description of aripiprazole were selected. DATA SYNTHESIS: Aripiprazole is a dopamine partial agonist and a serotonin-2A antagonist; it is dosed 10-30 mg/d, with no initial titration necessary. Short-term clinical trials demonstrated efficacy in acute exacerbations, and long-term studies showed that aripiprazole can maintain remission of schizophrenia. Most adverse events were mild. The incidence of extrapyramidal symptoms was low, with akathisia being the most common. CONCLUSIONS: Aripiprazole currently demonstrates comparable efficacy and safety for use in schizophrenia.

Expert Opin Investig Drugs. 2003 Apr;12(4):655-62. : Aripiprazole: a partial dopamine D2 receptor agonist antipsychotic.
Keck PE Jr, McElroy SL.
Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine and General Clinical Research Center, Mental Health Service Line, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
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.

Psychopharmacology (Berl). 2003 Apr;166(4):391-9. Epub 2003 Feb 28.: Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study.
Casey DE, Carson WH, Saha AR, Liebeskind A, Ali MW, Jody D, Ingenito GG; Aripiprazole Study Group.
Mental Health Division (P3MIRECC), VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.
daniel.casey@med.va.gov
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.

Int J Clin Pract. 2003 Jan-Feb;57(1):49-54. : Aripiprazole: a review of its pharmacology and clinical use.
Taylor DM.
Maudsley Hospital, London, UK.
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.

J Pharmacol Exp Ther. 2002 Jul;302(1):381-9. : Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors.
Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB.
Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
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.

Eur J Pharmacol. 2002 Apr 26;441(3):137-40. : The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor.
Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA.
Neuroscience Department, Maryland Research Laboratories, Otsuka Maryland Research Institute, 9900 Medical Center Drive, Rockville, MD 20850, USA.
shaunj@otsuka.com
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.