Apiz - Summary of Clinical Trials on Aripiprazole
Apiz - Summary of Clinical Trials on Aripiprazole
GENERIC NAME: aripiprazole
BRAND NAME: Apiz (Reliance Formulation)
DRUG CLASS AND MECHANISM:
Aripiprazole is an anti-psychotic drug for treating psychoses. Like other anti-psychotic drugs, the mechanism of action of aripiprazole is unknown. Moreover, like other anti-psychotics, it blocks several receptors on the nerves of the brain for several neurotransmitters (chemicals that nerves use to communicate with each other). It is thought that its beneficial effect is due to its effects on dopamine and serotonin receptors. Its effects on these receptors are complex, involving stimulation of the receptors but to a lesser degree than the naturally occurring neurotransmitters (a process called partial agonism). The FDA approved aripiprazole as a treatment for schizophrenia in November of 2002.
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ARIPIPRAZOLE (Apiz):
Emerging as Next Great Hope for Schizophrenia
Editor's note: My son was diagnosed with schizophrenia in 1999 at the age of eighteen. We tried risperidone, ziprasidone, quetiapine, and clozapine without success or reduction of voices and symptoms, in fact, things just got worse. In December 2002, he switched to aripiprazole. Almost immediately there was a dramatic improvement, which has continued until today. Now he is more independent, has a renewed interest in life, has returned to college, and has an active social life. Things that previously were beyond our wildest hopes are now routine for him. Do not give up the search for something that works, every patient is unique! (June 2004)
Aripiprazole is being touted as the first member of the new generation of atypical antipsychotic drugs. This once-daily novel antipsychotic has undergone a number of studies, revealing that aripiprazole is significantly better at controlling both the positive and negative symptoms of schizophrenia than placebo and has equaled haloperidol and risperidone in its ability to control these symptoms.
On October 31, 2001, Bristol-Myers Squibb and Otsuka Pharmaceutical Co. filed a New Drug Application (NDA) with the FDA and the two companies anticipate the launch of aripiprazole late in the third quarter of 2002.
Stephen M. Stahl, M.D., Ph.D., Professor of Psychiatry at the University of California at San Diego, places aripiprazole in the class of antipsychotics called dopamine system stabilizers (DSSs). Stahl dubs these new therapeutic agents “Goldilocks” because of their ability to strike a balance between too much and too little dopamine. With “just right” result, negative and cognitive symptoms are reduced and motor side effects or prolactin elevation is absent.
Previous atypical drugs block dopamine D2 receptors resulting in motor side effects such as pseudo-parkinsonism, and ultimately tardive dyskinesia.
Robert McQuade, Ph.D., director of Global Medical Marketing for Bristol-Myers Squibb, cites the evolution of antipsychotic medications and how their mechanisms of action have changed over time. “The big disadvantage was the side effects,” he says. “The atypicals were designed to address symptoms such as EPS, but brought about different side effects.” Each drug within the atypical category elicited its own particular adverse event, according to McQuade. Literature suggests, he says, that olanzapine causes weight gain, ziprasidone increases the QTc interval and risperidone increases plasma prolactin.
“These drugs solved some problems, but created others.” “From a psychopharmacologic viewpoint, aripiprazole is bringing new science to the field,” he says. Unlike the older atypical antipsychotics that reduce positive symptoms of psychosis, such as delusions and hallucinations, by blocking D2 receptors, aripiprazole stabilizes or modulates them. McQuade underscores the multi-faceted benefits of aripiprazole based on the results of several controlled trials, some of which lasted up to 52 weeks in duration, involving more than 3,400 patients with schizophrenia. Aripiprazole was statistically superior to placebo on positive and negative symptoms and superior to haloperidol for negative symptoms, according to McQuade. “Aripiprazole delivers a package of tolerability that enhances the benefit to the patient and thus enhances compliance,” he concludes.
Potential problem with akathisia
According to Larry Ereshefsky, Pharm.D., professor of pharmacy, pharmacology and psychiatry at the University of Texas Health Science Center at San Antonio, the novel partial dopamine agonist mechanism of action augments the 5-Htla and 5-HT2 effects of aripiprazole. “These effects should lead to greater dopaminergic throughput and cortical activity which is good for thinking,” says Ereshefsky. “But it also might possibly explain the increased rates of akathisia at the middle doses (15 mg/d) in some studies. There is clearly a greater effect on the Barnes akathisia scale than from risperidone, and about half the effect of haloperidol.” Ereshefsy adds, “Akathisia is a potential side effect which bares further evaluation in long-term studies to see whether it abates.”
(Akathisia is having a feeling of inner restlessness and the urge to move, rocking while standing or sitting, lifting of the feet as if marching on the spot, and crossing and uncrossing of the legs while sitting)
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Title: New Antipsychotic Aripiprazole Shows Promise for Acute Mania: Presented at APA
"New Antipsychotic Aripiprazole Shows Promise for Acute Mania: Presented at APA"
By Alison Palkhivala PHILADELPHIA, PA -- May 23, 2002 --
Aripiprazole, a new investigational antipsychotic drug, is showing promise for the treatment of acute mania in patients with bipolar disorder. Studies on the drug were presented here this week at the annual meeting of the American Psychiatric Association (APA). As part of a phase III, multicenter, double-blind, randomized, placebo-controlled trial, 262 patients diagnosed with acute mania were treated with either aripiprazole or placebo. The study's lead author was Paul E. Keck Jr., MD, from the department of psychiatry at the University of Cincinnati College of Medicine in Cincinnati, Ohio. On day 4, patients in the treatment group began to show more improvement than the placebo group with respect to acute manic symptoms. These included elevated mood, irritability, thought disorder, abnormal thought content, and disruptive-aggressive behavior. A significant difference was also found between the two groups with respect to mean change from baseline on the total score of the Young Mania Rating Scale (Y-MRS), with the aripiprazole group showing more improvement than the placebo group. This difference increased as the three-week trial progressed. Response to therapy was defined as a decrease of 50 percent or more in Y-MRS total score. Based on this criterion, 40 percent of patients on aripiprazole responded to treatment compared to 19 percent on placebo. A second placebo-controlled study of aripiprazole did not reveal a difference between the drug and a placebo with respect to response rate. However, response rate in the placebo group was abnormally high: both the treatment and placebo groups had response rates of 40 percent. The most common side effects associated with aripiprazole therapy were headache, nausea, dyspepsia, somnolence, and agitation. Most side effects began early in treatment and few lasted more than a week. Aripiprazole has a mechanism of action that is different from other antipsychotic drugs, affecting both dopamine and serotonin receptors. It is the product of a cooperative effort between Bristol-Myers Squibb and Otsuka Pharmaceuticals. Together, they filed a regulatory applications in the US and Europe in 2001 for the drug to be approved for the treatment of schizophrenia.
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Title: Aripiprazole for Long-Term Maintenance Treatment in Schizophrenia: Presented at APA
"Aripiprazole for Long-Term Maintenance Treatment in Schizophrenia: Presented at APA"
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 --
The investigative antipsychotic drug aripiprazole produced improvements in positive, negative and depressive symptoms of schizophrenia during a 52-week study, researchers reported at the annual meeting of the American Psychiatric Association (APA). "Beyond the short-term clinical trials that have demonstrated acute efficacy, this study looks at aripiprazole in more long-term or maintenance treatment for schizophrenia. This is a chronic disorder with frequent relapses. In this study we looked at patients having acute relapses of their illness, at their stabilization with aripiprazole and then maintenance of the efficacy of the effect of this treatment over a one-year period," said Mary J. Kujawa, MD, medical director of US neuroscience medical affairs at Bristol-Myers Squibb Company in Princeton, New Jersey. The mechanism of action of aripiprazole appears to be different from other available antipsychotics. Aripiprazole shows potent partial agonism of D2 dopamine receptors, partial agonism of 5HT1A serotonin receptors and antagonism of 5HT2A serotonin receptors. Partial agonism means that aripiprazole blocks the receptor if it is overstimulated and stimulates it if it when activity is needed. The investigators in this multicenter, randomized, double-blind study recruited 1,294 subjects suffering an acute relapse of chronic schizophrenia. They randomized 861subjects to aripiprazole 30 mg/day and 433 to haloperidol 10 mg/day. They allowed a one-time dose reduction to aripiprazole 20 mg/day and haloperidol 7 mg/day. The investigators used Positive and Negative Symptoms for Schizophrenia (PANSS) and the Montgomery-Asberg Depression Rating Scale (MADRS) scores to evaluate efficacy throughout the study. Compared to the haloperidol cohort, a much larger percentage of patients treated with aripiprazole showed a therapeutic response and remained in treatment at weeks 8, 26, and 52 (week 52: 40 percent vs. 27 percent, p<0.001). Compared to haloperidol, aripiprazole elicited statistically significant improvements in the PANSS negative subscale and in depressive symptoms as shown in the MADRS. Extrapyramidal effect-related adverse events were significantly lower with aripiprazole than with haloperidol (p<0.001). Weight gain was comparable in both groups of subjects. QTc interval were also comparable between the groups. "One of the most difficult challenges in treating patients with schizophrenia is long-term adherence," said Jeffrey Lieberman, MD, professor of psychiatry and pharmacology at the University of North Carolina Medical School in Chapel Hill. "Data from this study suggests the potential for significant benefits of aripiprazole in the long-term treatment of schizophrenia, a chronic mental illness that affects approximately 1 percent of the world's population."
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Title: Switching to Aripiprazole Safe and Effective in Schizophrenia: Presented at APA
By Alison Palkhivala PHILADELPHIA, PA -- May 23, 2002 --
Switching schizophrenic patients to new antipsychotic aripiprazole from both conventional and atypical antipsychotics appears to be both safe and well tolerated. For the study, 311 stable schizophrenic patients taking olanzapine, risperidone, or haloperidol were switched to aripiprazole using one of three switching strategies. These strategies consisted of a switch to a full dose of aripiprazole without titration from prior antipsychotic treatment, switching to a full dose of aripiprazole along with tapering of the previous treatment for two weeks, or switching to aripiprazole with titration up along with titration down of the previous medication over two weeks. The study was led by Daniel E. Casey, MD, from the Mental Illness Research, Education, and Clinical Center of the Portland Veterans Affairs Medical Center in Oregon. The study was presented here this week at the annual meeting of the American Psychiatric Association (APA). Regardless of the switching strategy employed, the switching process was generally safe and well tolerated. Eight weeks after switching to aripiprazole, patients showed improvements in extrapyramidal symptoms (EPS) and reductions in prolactin levels and weight. They also showed statistically significant improvements in the Positive and Negative Syndrome Scale (PANSS). Patients switched from olanzapine showed a statistically significant weight loss of 2.03 kg (p<0.001) as well as a decrease in prolactin levels and improvement in EPS. Those switched from risperidone also had statistically significant decreases in prolactin levels (p<0.001), as well as reductions in weight and EPS. Those switched from haloperidol had improvements in EPS and decreased prolactin levels. Aripiprazole was generally well-tolerated, with the most common side effect being insomnia. Most side effects were mild to moderate. Aripiprazole, a novel antipsychotic, is jointly produced by Bristol-Myers Squibb and Otsuka Pharmaceuticals. In 2001, they submitted the drug for approval to regulatory agencies in the United States and Europe.
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Title: Aripiprazole Versus Placebo in the Treatment of Chronic Schizophrenia: Presented at APA
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 --
The investigative drug aripiprazole provides effective and safe antipsychotic treatment in patients with chronic schizophrenia, researchers reported here this week at the annual meeting of the American Psychiatric Association (APA). "The most important implication of this study is that it shows that aripiprazole is effective in significantly reducing the time-to-relapse as well as the rate of relapse in patients with schizophrenia who are being treated with medication," said lead investigator Teresa Pigott, MD, director of clinical trials in the department of psychiatry at the University of Florida School of Medicine in Gainesville, Florida. The purpose of the study was to assess the time to relapse with aripiprazole, compared to placebo, over 26 weeks in stable patients with chronic schizophrenia. The multicenter, randomized, double-blind, placebo-controlled study enrolled 310 subjects with chronic schizophrenia who were evaluated as stable, with no significant improvement or worsening in the previous three months and baseline on the Positive and Negative Symptoms for Schizophrenia (PANSS) scale of 82. They were randomized to aripiprazole 15 mg/day or placebo. Efficacy was determined by time to relapse, PANSS Total Score, and Clinical Global Improvement (CGI) score. Significantly fewer patients in the aripiprazole group (34 percent) relapsed by study end point compared to placebo (57 percent). Aripiprazole also increased the time to relapse by two fold. The agent was well tolerated , with an adverse events rate comparable to placebo, the researchers found. No significant changes occurred in Simpson-Angus Scale (SAS), Involuntary Movement Scale (AIMS), and Barnes Akathisia scores in either group. Weight gain in the aripiprazole group was comparable to placebo, Dr. Pigott said.
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Title: Meta-Analysis of the Efficacy of Aripiprazole in Schizophrenia: Presented at APA
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 –
Aripiprazole improves positive and negative symptoms of schizophrenia, with significant effects appearing one week after initiation of treatment. "The most important implication of this study is that aripiprazole 15 mg is shown to be effective in the treatment of schizophrenia. We also saw replicative efficacy in one or more studies in doses of 15 mg and above," said co-investigator William Carson, MD, group director in research and development at Bristol-Myers Squibb Research Institute in Wallingford, Connecticut. The presentation was made at the annual meeting of the American Psychiatric Association (APA). The meta-analysis included four- to six-week multicenter, double-blind, fixed-dose, placebo-controlled studies involving a total of 1,545 patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder. The investigators randomized 898 subjects to aripiprazole, 381 to placebo, and the rest to active control: 167 to haloperidol 10 mg/day and 99 to risperidone 6 mg/day. Daily aripiprazole doses ranged from 2-30 mg. Weekly efficacy assessments included Positive and Negative Symptoms for Schizophrenia (PANSS) and Clinical Global Impression (CGI) scales. In the meta-analysis, aripiprazole showed superior efficacy to placebo at doses over 2 mg. The researchers also noted that aripiprazole dosing over 2 mg elicited significant improvement in PANSS-total score by week 1 (p<0.05). In examining the individual studies, the researchers found that aripiprazole dosing at 15 mg, 20 mg and 30 mg consistently produced significant improvements in PANSS-total score. They found similar PANSS-score changes from baseline for all aripiprazole groups. Across all of the studies, aripiprazole 15 mg, 20 mg and 30 mg produced significant improvements in other efficacy scores compared with placebo. In studies with active control, haloperidol and risperidone separated from placebo. "We had active comparator arms. Two of the active comparator drugs were haloperidol and risperidone. We saw efficacy that was comparable between aripiprazole and a typical antipsychotic, haloperidol, as well as an atypical antipsychotic, risperidone." Dr. Carson added. The study was supported by Bristol-Myers-Squibb.
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The Canadian Journal of Psychiatry (CJP) – February 2004
Aripirazole–Olanzapine Combination for Treatment of Schizophrenia
Dear Editor:
Recent literature is equivocal about antipsychotic combination in schizophrenia (1). However, the advent of the new antipsychotic aripiprazole, which has a mechanism of action different from other atypical antipsychotics, rekindles interest in this field. I describe a patient with schizophrenia showing partial response to olanzapine alone, but showing a marked improvement in symptoms (particularly the negative symptoms) on augmentation with aripiprazole. The possible mechanism of aripiprazole’s efficacy in negative symptoms is discussed.
Case Report
Mrs A, a 47-year-old woman with a long-standing history of schizophrenia, was admitted with a psychotic exacerbation precipitated by discontinuation of medicines. On mental status examination, she had marked psychomotor retardation, poverty of speech, flat affect, persecutory and referential delusions, loosening of association, and poor insight and judgment. She scored 122 on the Positive and Negative Symptom Scale (PANSS) with predominant negative symptoms (negative score 46, positive score 25). The patient was restarted on her previous antipsychotic; namely, olanzapine titrated to 20 mg daily, with further increase precluded by increased sedation. Despite 6 weeks on this dosage of olanzapine, there was modest improvement in positive symptoms but none at all in negative symptoms. In view of her partial response to olanzapine, aripiprazole was added at 15 mg daily as an augmenting agent. Within 2 weeks of this addition, the patient began to show improvement in her symptomatology. Her PANSS score dropped to 54 (a drop of 56%) after 6 weeks of olanzapine and aripiprazole combined. The positive, negative, and general psychopathology score decreased by 50%, 69%, and 45%, respectively. The patient was discharged on this combination and continues to maintain her improvement 2 months after discharge, at the same dosage of the 2 drugs. The notable improvement in negative symptoms deserves further attention; possible mechanisms are discussed below.
Olanzapine has a D2 receptor occupancy of 71% to 80% in the usual clinical dosage range of 10 to 20 mg daily, with the occupancy rising with dosage increase (2). Aripiprazole also shows a dose- dependent D2 receptor occupancy above 85% at dosages of 10 to 30 mg daily (3). With both olanzapine and aripiprazole having a high D2 receptor occupancy, one may question the rationale of combining these drugs. However, even at D2 occupancy values above 90%, extrapyramidal symptoms (EPS) are not observed with aripirazole (3). This may be attributed to aripiprazole’s being a partial agonist at the D2 autoreceptor. It would be interesting to explore how this mechanism may contribute toward improvement in negative symptoms.
Negative symptoms of schizophrenia have been hypothesized to result from a decrease in tonic dopamine transmission (4). Further, D2 autoreceptors tonically inhibit dopaminergic neurons (5). Stimulation of these receptors, as is the case with aripiprazole, induces their desensitization, leading to increased dopamine release (4). This novel mechanism may underlie aripiprazole’s low propensity to cause EPS and may also contribute toward its possible efficacy in negative symptoms. The previous generation of atypical antipsychotics, including clozapine, relies mainly on 5-HT2A antagonism for their greater efficacy in negative symptoms (6). Though aripiprazole also has a 5-HT2A antagonistic action, its role as a dopamine autoreceptor agonist may provide additional benefits for countering negative symptoms. Indeed, the study by Kane and colleagues showed that 15 mg daily, but not 30 mg daily, of aripiprazole produced a significantly greater improvement in PANSS negative subscale score, compared with placebo (7). There is some evidence to suggest that dopamine autoreceptor agonists do improve negative symptoms in schizophrenia patients with predominant negative symptoms (8). As aripiprazole acts as a dopamine agonist in the presence of significant receptor reserve for dopamine (which may be secondary to receptor upregulation following a hypodopaminergic state) (9), it can be speculated that schizophrenia patients with residual negative symptoms who are on potent D2 antagonists may benefit from the addition of small doses of aripiprazole. Further studies of aripiprazole at lower and higher dosages in primary negative symptoms are encouraged.
References
1. Freudenreich O, Goff DC. Antipsychotic combination in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002;106:323–30.
2. Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA, and others. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 1998;155:921–8.
3. Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF, and others. 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;27:248–59.
4. Moore H, West AR, Grace AA. The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry 1999;46:40–55.
5. Millan MJ, Gobert A, Newman-Tancredi A, Lejuene F, Cussac D, Rivet JM, and others. S33084, a novel, potent, selective, and competitive antagonist at dopamine D3-receptors: I. Receptor, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 2000; 293:1048–62.
6. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21(Suppl 2):106S–15S.
7. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito G, Zimbroff DL, and others. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763–71.
8. Wetzel H, Hillert A, Grunder G, Benkert O. Roxindole, a dopamine autoreceptor agonist, in the treatment of positive and negative schizophrenic symptoms. Am J Psychiatry 1994; 151:1499–2.
Harpreet S Duggal, MD, DPMPittsburgh,USA
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Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder
.Swainston Harrison T, Perry CM.Adis International Limited, Auckland, New Zealand.
Demail@adis.co.nz
Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia. Aripiprazole 10 or 15 mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (> or =1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia.
Pharmacological properties:
Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1A, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole's partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1A receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound. Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15 mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours. Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein. Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased).
Therapeutic Efficacy:
The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment. The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomized trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients. Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neuro-cognitive parameters evaluated compared with recipients of olanzapine 10-15 mg/day.
Tolerability:
Aripiprazole 10-30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial). In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%). Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial.
For further information, you can contact the following gentlemen:
Mr. Mukesh Vankani - General Manager (Cell# 09825032571) OR
Mr. Dipak Shah B.Pharm. MBA
at
reliancehealthcare@yahoo.co.in
GENERIC NAME: aripiprazole
BRAND NAME: Apiz (Reliance Formulation)
DRUG CLASS AND MECHANISM:
Aripiprazole is an anti-psychotic drug for treating psychoses. Like other anti-psychotic drugs, the mechanism of action of aripiprazole is unknown. Moreover, like other anti-psychotics, it blocks several receptors on the nerves of the brain for several neurotransmitters (chemicals that nerves use to communicate with each other). It is thought that its beneficial effect is due to its effects on dopamine and serotonin receptors. Its effects on these receptors are complex, involving stimulation of the receptors but to a lesser degree than the naturally occurring neurotransmitters (a process called partial agonism). The FDA approved aripiprazole as a treatment for schizophrenia in November of 2002.
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ARIPIPRAZOLE (Apiz):
Emerging as Next Great Hope for Schizophrenia
Editor's note: My son was diagnosed with schizophrenia in 1999 at the age of eighteen. We tried risperidone, ziprasidone, quetiapine, and clozapine without success or reduction of voices and symptoms, in fact, things just got worse. In December 2002, he switched to aripiprazole. Almost immediately there was a dramatic improvement, which has continued until today. Now he is more independent, has a renewed interest in life, has returned to college, and has an active social life. Things that previously were beyond our wildest hopes are now routine for him. Do not give up the search for something that works, every patient is unique! (June 2004)
Aripiprazole is being touted as the first member of the new generation of atypical antipsychotic drugs. This once-daily novel antipsychotic has undergone a number of studies, revealing that aripiprazole is significantly better at controlling both the positive and negative symptoms of schizophrenia than placebo and has equaled haloperidol and risperidone in its ability to control these symptoms.
On October 31, 2001, Bristol-Myers Squibb and Otsuka Pharmaceutical Co. filed a New Drug Application (NDA) with the FDA and the two companies anticipate the launch of aripiprazole late in the third quarter of 2002.
Stephen M. Stahl, M.D., Ph.D., Professor of Psychiatry at the University of California at San Diego, places aripiprazole in the class of antipsychotics called dopamine system stabilizers (DSSs). Stahl dubs these new therapeutic agents “Goldilocks” because of their ability to strike a balance between too much and too little dopamine. With “just right” result, negative and cognitive symptoms are reduced and motor side effects or prolactin elevation is absent.
Previous atypical drugs block dopamine D2 receptors resulting in motor side effects such as pseudo-parkinsonism, and ultimately tardive dyskinesia.
Robert McQuade, Ph.D., director of Global Medical Marketing for Bristol-Myers Squibb, cites the evolution of antipsychotic medications and how their mechanisms of action have changed over time. “The big disadvantage was the side effects,” he says. “The atypicals were designed to address symptoms such as EPS, but brought about different side effects.” Each drug within the atypical category elicited its own particular adverse event, according to McQuade. Literature suggests, he says, that olanzapine causes weight gain, ziprasidone increases the QTc interval and risperidone increases plasma prolactin.
“These drugs solved some problems, but created others.” “From a psychopharmacologic viewpoint, aripiprazole is bringing new science to the field,” he says. Unlike the older atypical antipsychotics that reduce positive symptoms of psychosis, such as delusions and hallucinations, by blocking D2 receptors, aripiprazole stabilizes or modulates them. McQuade underscores the multi-faceted benefits of aripiprazole based on the results of several controlled trials, some of which lasted up to 52 weeks in duration, involving more than 3,400 patients with schizophrenia. Aripiprazole was statistically superior to placebo on positive and negative symptoms and superior to haloperidol for negative symptoms, according to McQuade. “Aripiprazole delivers a package of tolerability that enhances the benefit to the patient and thus enhances compliance,” he concludes.
Potential problem with akathisia
According to Larry Ereshefsky, Pharm.D., professor of pharmacy, pharmacology and psychiatry at the University of Texas Health Science Center at San Antonio, the novel partial dopamine agonist mechanism of action augments the 5-Htla and 5-HT2 effects of aripiprazole. “These effects should lead to greater dopaminergic throughput and cortical activity which is good for thinking,” says Ereshefsky. “But it also might possibly explain the increased rates of akathisia at the middle doses (15 mg/d) in some studies. There is clearly a greater effect on the Barnes akathisia scale than from risperidone, and about half the effect of haloperidol.” Ereshefsy adds, “Akathisia is a potential side effect which bares further evaluation in long-term studies to see whether it abates.”
(Akathisia is having a feeling of inner restlessness and the urge to move, rocking while standing or sitting, lifting of the feet as if marching on the spot, and crossing and uncrossing of the legs while sitting)
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Title: New Antipsychotic Aripiprazole Shows Promise for Acute Mania: Presented at APA
"New Antipsychotic Aripiprazole Shows Promise for Acute Mania: Presented at APA"
By Alison Palkhivala PHILADELPHIA, PA -- May 23, 2002 --
Aripiprazole, a new investigational antipsychotic drug, is showing promise for the treatment of acute mania in patients with bipolar disorder. Studies on the drug were presented here this week at the annual meeting of the American Psychiatric Association (APA). As part of a phase III, multicenter, double-blind, randomized, placebo-controlled trial, 262 patients diagnosed with acute mania were treated with either aripiprazole or placebo. The study's lead author was Paul E. Keck Jr., MD, from the department of psychiatry at the University of Cincinnati College of Medicine in Cincinnati, Ohio. On day 4, patients in the treatment group began to show more improvement than the placebo group with respect to acute manic symptoms. These included elevated mood, irritability, thought disorder, abnormal thought content, and disruptive-aggressive behavior. A significant difference was also found between the two groups with respect to mean change from baseline on the total score of the Young Mania Rating Scale (Y-MRS), with the aripiprazole group showing more improvement than the placebo group. This difference increased as the three-week trial progressed. Response to therapy was defined as a decrease of 50 percent or more in Y-MRS total score. Based on this criterion, 40 percent of patients on aripiprazole responded to treatment compared to 19 percent on placebo. A second placebo-controlled study of aripiprazole did not reveal a difference between the drug and a placebo with respect to response rate. However, response rate in the placebo group was abnormally high: both the treatment and placebo groups had response rates of 40 percent. The most common side effects associated with aripiprazole therapy were headache, nausea, dyspepsia, somnolence, and agitation. Most side effects began early in treatment and few lasted more than a week. Aripiprazole has a mechanism of action that is different from other antipsychotic drugs, affecting both dopamine and serotonin receptors. It is the product of a cooperative effort between Bristol-Myers Squibb and Otsuka Pharmaceuticals. Together, they filed a regulatory applications in the US and Europe in 2001 for the drug to be approved for the treatment of schizophrenia.
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Title: Aripiprazole for Long-Term Maintenance Treatment in Schizophrenia: Presented at APA
"Aripiprazole for Long-Term Maintenance Treatment in Schizophrenia: Presented at APA"
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 --
The investigative antipsychotic drug aripiprazole produced improvements in positive, negative and depressive symptoms of schizophrenia during a 52-week study, researchers reported at the annual meeting of the American Psychiatric Association (APA). "Beyond the short-term clinical trials that have demonstrated acute efficacy, this study looks at aripiprazole in more long-term or maintenance treatment for schizophrenia. This is a chronic disorder with frequent relapses. In this study we looked at patients having acute relapses of their illness, at their stabilization with aripiprazole and then maintenance of the efficacy of the effect of this treatment over a one-year period," said Mary J. Kujawa, MD, medical director of US neuroscience medical affairs at Bristol-Myers Squibb Company in Princeton, New Jersey. The mechanism of action of aripiprazole appears to be different from other available antipsychotics. Aripiprazole shows potent partial agonism of D2 dopamine receptors, partial agonism of 5HT1A serotonin receptors and antagonism of 5HT2A serotonin receptors. Partial agonism means that aripiprazole blocks the receptor if it is overstimulated and stimulates it if it when activity is needed. The investigators in this multicenter, randomized, double-blind study recruited 1,294 subjects suffering an acute relapse of chronic schizophrenia. They randomized 861subjects to aripiprazole 30 mg/day and 433 to haloperidol 10 mg/day. They allowed a one-time dose reduction to aripiprazole 20 mg/day and haloperidol 7 mg/day. The investigators used Positive and Negative Symptoms for Schizophrenia (PANSS) and the Montgomery-Asberg Depression Rating Scale (MADRS) scores to evaluate efficacy throughout the study. Compared to the haloperidol cohort, a much larger percentage of patients treated with aripiprazole showed a therapeutic response and remained in treatment at weeks 8, 26, and 52 (week 52: 40 percent vs. 27 percent, p<0.001). Compared to haloperidol, aripiprazole elicited statistically significant improvements in the PANSS negative subscale and in depressive symptoms as shown in the MADRS. Extrapyramidal effect-related adverse events were significantly lower with aripiprazole than with haloperidol (p<0.001). Weight gain was comparable in both groups of subjects. QTc interval were also comparable between the groups. "One of the most difficult challenges in treating patients with schizophrenia is long-term adherence," said Jeffrey Lieberman, MD, professor of psychiatry and pharmacology at the University of North Carolina Medical School in Chapel Hill. "Data from this study suggests the potential for significant benefits of aripiprazole in the long-term treatment of schizophrenia, a chronic mental illness that affects approximately 1 percent of the world's population."
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Title: Switching to Aripiprazole Safe and Effective in Schizophrenia: Presented at APA
By Alison Palkhivala PHILADELPHIA, PA -- May 23, 2002 --
Switching schizophrenic patients to new antipsychotic aripiprazole from both conventional and atypical antipsychotics appears to be both safe and well tolerated. For the study, 311 stable schizophrenic patients taking olanzapine, risperidone, or haloperidol were switched to aripiprazole using one of three switching strategies. These strategies consisted of a switch to a full dose of aripiprazole without titration from prior antipsychotic treatment, switching to a full dose of aripiprazole along with tapering of the previous treatment for two weeks, or switching to aripiprazole with titration up along with titration down of the previous medication over two weeks. The study was led by Daniel E. Casey, MD, from the Mental Illness Research, Education, and Clinical Center of the Portland Veterans Affairs Medical Center in Oregon. The study was presented here this week at the annual meeting of the American Psychiatric Association (APA). Regardless of the switching strategy employed, the switching process was generally safe and well tolerated. Eight weeks after switching to aripiprazole, patients showed improvements in extrapyramidal symptoms (EPS) and reductions in prolactin levels and weight. They also showed statistically significant improvements in the Positive and Negative Syndrome Scale (PANSS). Patients switched from olanzapine showed a statistically significant weight loss of 2.03 kg (p<0.001) as well as a decrease in prolactin levels and improvement in EPS. Those switched from risperidone also had statistically significant decreases in prolactin levels (p<0.001), as well as reductions in weight and EPS. Those switched from haloperidol had improvements in EPS and decreased prolactin levels. Aripiprazole was generally well-tolerated, with the most common side effect being insomnia. Most side effects were mild to moderate. Aripiprazole, a novel antipsychotic, is jointly produced by Bristol-Myers Squibb and Otsuka Pharmaceuticals. In 2001, they submitted the drug for approval to regulatory agencies in the United States and Europe.
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Title: Aripiprazole Versus Placebo in the Treatment of Chronic Schizophrenia: Presented at APA
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 --
The investigative drug aripiprazole provides effective and safe antipsychotic treatment in patients with chronic schizophrenia, researchers reported here this week at the annual meeting of the American Psychiatric Association (APA). "The most important implication of this study is that it shows that aripiprazole is effective in significantly reducing the time-to-relapse as well as the rate of relapse in patients with schizophrenia who are being treated with medication," said lead investigator Teresa Pigott, MD, director of clinical trials in the department of psychiatry at the University of Florida School of Medicine in Gainesville, Florida. The purpose of the study was to assess the time to relapse with aripiprazole, compared to placebo, over 26 weeks in stable patients with chronic schizophrenia. The multicenter, randomized, double-blind, placebo-controlled study enrolled 310 subjects with chronic schizophrenia who were evaluated as stable, with no significant improvement or worsening in the previous three months and baseline on the Positive and Negative Symptoms for Schizophrenia (PANSS) scale of 82. They were randomized to aripiprazole 15 mg/day or placebo. Efficacy was determined by time to relapse, PANSS Total Score, and Clinical Global Improvement (CGI) score. Significantly fewer patients in the aripiprazole group (34 percent) relapsed by study end point compared to placebo (57 percent). Aripiprazole also increased the time to relapse by two fold. The agent was well tolerated , with an adverse events rate comparable to placebo, the researchers found. No significant changes occurred in Simpson-Angus Scale (SAS), Involuntary Movement Scale (AIMS), and Barnes Akathisia scores in either group. Weight gain in the aripiprazole group was comparable to placebo, Dr. Pigott said.
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Title: Meta-Analysis of the Efficacy of Aripiprazole in Schizophrenia: Presented at APA
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 –
Aripiprazole improves positive and negative symptoms of schizophrenia, with significant effects appearing one week after initiation of treatment. "The most important implication of this study is that aripiprazole 15 mg is shown to be effective in the treatment of schizophrenia. We also saw replicative efficacy in one or more studies in doses of 15 mg and above," said co-investigator William Carson, MD, group director in research and development at Bristol-Myers Squibb Research Institute in Wallingford, Connecticut. The presentation was made at the annual meeting of the American Psychiatric Association (APA). The meta-analysis included four- to six-week multicenter, double-blind, fixed-dose, placebo-controlled studies involving a total of 1,545 patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder. The investigators randomized 898 subjects to aripiprazole, 381 to placebo, and the rest to active control: 167 to haloperidol 10 mg/day and 99 to risperidone 6 mg/day. Daily aripiprazole doses ranged from 2-30 mg. Weekly efficacy assessments included Positive and Negative Symptoms for Schizophrenia (PANSS) and Clinical Global Impression (CGI) scales. In the meta-analysis, aripiprazole showed superior efficacy to placebo at doses over 2 mg. The researchers also noted that aripiprazole dosing over 2 mg elicited significant improvement in PANSS-total score by week 1 (p<0.05). In examining the individual studies, the researchers found that aripiprazole dosing at 15 mg, 20 mg and 30 mg consistently produced significant improvements in PANSS-total score. They found similar PANSS-score changes from baseline for all aripiprazole groups. Across all of the studies, aripiprazole 15 mg, 20 mg and 30 mg produced significant improvements in other efficacy scores compared with placebo. In studies with active control, haloperidol and risperidone separated from placebo. "We had active comparator arms. Two of the active comparator drugs were haloperidol and risperidone. We saw efficacy that was comparable between aripiprazole and a typical antipsychotic, haloperidol, as well as an atypical antipsychotic, risperidone." Dr. Carson added. The study was supported by Bristol-Myers-Squibb.
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The Canadian Journal of Psychiatry (CJP) – February 2004
Aripirazole–Olanzapine Combination for Treatment of Schizophrenia
Dear Editor:
Recent literature is equivocal about antipsychotic combination in schizophrenia (1). However, the advent of the new antipsychotic aripiprazole, which has a mechanism of action different from other atypical antipsychotics, rekindles interest in this field. I describe a patient with schizophrenia showing partial response to olanzapine alone, but showing a marked improvement in symptoms (particularly the negative symptoms) on augmentation with aripiprazole. The possible mechanism of aripiprazole’s efficacy in negative symptoms is discussed.
Case Report
Mrs A, a 47-year-old woman with a long-standing history of schizophrenia, was admitted with a psychotic exacerbation precipitated by discontinuation of medicines. On mental status examination, she had marked psychomotor retardation, poverty of speech, flat affect, persecutory and referential delusions, loosening of association, and poor insight and judgment. She scored 122 on the Positive and Negative Symptom Scale (PANSS) with predominant negative symptoms (negative score 46, positive score 25). The patient was restarted on her previous antipsychotic; namely, olanzapine titrated to 20 mg daily, with further increase precluded by increased sedation. Despite 6 weeks on this dosage of olanzapine, there was modest improvement in positive symptoms but none at all in negative symptoms. In view of her partial response to olanzapine, aripiprazole was added at 15 mg daily as an augmenting agent. Within 2 weeks of this addition, the patient began to show improvement in her symptomatology. Her PANSS score dropped to 54 (a drop of 56%) after 6 weeks of olanzapine and aripiprazole combined. The positive, negative, and general psychopathology score decreased by 50%, 69%, and 45%, respectively. The patient was discharged on this combination and continues to maintain her improvement 2 months after discharge, at the same dosage of the 2 drugs. The notable improvement in negative symptoms deserves further attention; possible mechanisms are discussed below.
Olanzapine has a D2 receptor occupancy of 71% to 80% in the usual clinical dosage range of 10 to 20 mg daily, with the occupancy rising with dosage increase (2). Aripiprazole also shows a dose- dependent D2 receptor occupancy above 85% at dosages of 10 to 30 mg daily (3). With both olanzapine and aripiprazole having a high D2 receptor occupancy, one may question the rationale of combining these drugs. However, even at D2 occupancy values above 90%, extrapyramidal symptoms (EPS) are not observed with aripirazole (3). This may be attributed to aripiprazole’s being a partial agonist at the D2 autoreceptor. It would be interesting to explore how this mechanism may contribute toward improvement in negative symptoms.
Negative symptoms of schizophrenia have been hypothesized to result from a decrease in tonic dopamine transmission (4). Further, D2 autoreceptors tonically inhibit dopaminergic neurons (5). Stimulation of these receptors, as is the case with aripiprazole, induces their desensitization, leading to increased dopamine release (4). This novel mechanism may underlie aripiprazole’s low propensity to cause EPS and may also contribute toward its possible efficacy in negative symptoms. The previous generation of atypical antipsychotics, including clozapine, relies mainly on 5-HT2A antagonism for their greater efficacy in negative symptoms (6). Though aripiprazole also has a 5-HT2A antagonistic action, its role as a dopamine autoreceptor agonist may provide additional benefits for countering negative symptoms. Indeed, the study by Kane and colleagues showed that 15 mg daily, but not 30 mg daily, of aripiprazole produced a significantly greater improvement in PANSS negative subscale score, compared with placebo (7). There is some evidence to suggest that dopamine autoreceptor agonists do improve negative symptoms in schizophrenia patients with predominant negative symptoms (8). As aripiprazole acts as a dopamine agonist in the presence of significant receptor reserve for dopamine (which may be secondary to receptor upregulation following a hypodopaminergic state) (9), it can be speculated that schizophrenia patients with residual negative symptoms who are on potent D2 antagonists may benefit from the addition of small doses of aripiprazole. Further studies of aripiprazole at lower and higher dosages in primary negative symptoms are encouraged.
References
1. Freudenreich O, Goff DC. Antipsychotic combination in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002;106:323–30.
2. Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA, and others. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 1998;155:921–8.
3. Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF, and others. 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;27:248–59.
4. Moore H, West AR, Grace AA. The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry 1999;46:40–55.
5. Millan MJ, Gobert A, Newman-Tancredi A, Lejuene F, Cussac D, Rivet JM, and others. S33084, a novel, potent, selective, and competitive antagonist at dopamine D3-receptors: I. Receptor, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 2000; 293:1048–62.
6. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21(Suppl 2):106S–15S.
7. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito G, Zimbroff DL, and others. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763–71.
8. Wetzel H, Hillert A, Grunder G, Benkert O. Roxindole, a dopamine autoreceptor agonist, in the treatment of positive and negative schizophrenic symptoms. Am J Psychiatry 1994; 151:1499–2.
Harpreet S Duggal, MD, DPMPittsburgh,USA
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Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder
.Swainston Harrison T, Perry CM.Adis International Limited, Auckland, New Zealand.
Demail@adis.co.nz
Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia. Aripiprazole 10 or 15 mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (> or =1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia.
Pharmacological properties:
Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1A, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole's partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1A receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound. Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15 mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours. Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein. Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased).
Therapeutic Efficacy:
The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment. The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomized trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients. Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neuro-cognitive parameters evaluated compared with recipients of olanzapine 10-15 mg/day.
Tolerability:
Aripiprazole 10-30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial). In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%). Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial.
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