Posted by Sunnely on February 27, 2002, at 22:39:21
In reply to Aripiprazole--Cam or anyone know anything about it, posted by Chocoholic on February 27, 2002, at 20:35:04
Hope this helps.
Aripiprazole (Abilitat) 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.
Currently, aripiprazole is awaiting FDA approval. Bristol-Myers Squibb and Otsuka Pharmaceutical Co. Ltd filed a New Drug Application (NDA) with the United States FDA on October 31, 2001. The two companies anticipate the launch of aripiprazole late in the third quarter 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. (The common pharmacologic terminology for aripiprazole would be a partial dopamine agonist in contrast to other antipsychotic drugs that are dopamine antagonists.)
With a "just right" result, negative and cognitive symptoms are reduced and motor side side effects or prolactin elevation is absent. Previous atypical drugs block dopamine D2 receptors, mainly those in the mesolimbic dopamine pathway, according to Stahl. Since the blocking action is non-specific, D2 receptors in the nigrostriatal dopamine pathway are also hindered, resulting in motor side effects - i.e., (extrapyramidal symptoms [EPS] such as) pseudoparkinsonism, and ultimately, tardive dyskinesia.
The stabilization of the dopamine and serotonin systems is critical in managing the symptoms of schizophrenia. Stahl refers to his "Goldilocks" theory to explain the design of DSSs. They are meant to preserve or enhance dopaminergic neurotransmission where it is low ("too cold") and reduce it where it is too high ("too hot"), according to Stahl.
"In terms of treating psychosis, the goal is to reduce hyperactive dopamine neurons that mediate psychosis and at the same time enhance underactive dopamine neurons that mediate negative and cognitive symptoms (mesocortical pathway), while preserving physiologic function in dopamine neurons that regulate motor movement and prolactin - all in the same brain at the same time," he says.
Pharmacologically, the DSSs mechanism is known as partial agonist action, meaning activation at low dopaminergic tone and inhibition at high dopaminergic tone. The result is stabilized dopamine output. DSSs, including the prototypical aripiprazole, appear to be as effective in reducing psychosis as other antipsychotics, but without causing motor side effects in patients with schizophrenia.
CLINICAL TRIALS:
In a study comparing aripiprazole with placebo, the issue of efficacy was surpassed by the lack of adverse effects. While effectively managing the symptoms of schizophrenia, aripiprazole also demonstrated a significantly low incidence of side effects. QTc interval (electrocardiogram reading) did not change significantly from baseline in patients taking aripiprazole when compared to those on placebo. Only a small percentage of patients experienced weight gain, prolactin levels did not increase and extrapyramidal symptoms (EPS) were minimal. More importantly, since aripiprazole was well tolerated, few patients discontinued treatment. Any reported adverse events were minor - i.e., headache, agitation, insomnia and nervousness.In a study comparing aripiprazole with haloperidol and placebo, aripiprazole was administered in a double-blind, multi-center, four-week trial of 414 hospitalized patients with acute relapse of schizophrenia or schizoaffective disorder. Response rate was significantly superior to placebo, but the tolerability data suggest that aripiprazole may produce important advantages. As in the previously mentioned study, fewer EPS were reported, hyperprolactinemia, a typical condition resulting from antipsychotic use that may cause sexual dysfunction and loss of menstruation, was absent, and weight gain was minimal, as was sedation. Mild adverse events, such as nausea and dizziness, were reported.
DOSING AND DRUG INTERACTIONS:
The recommended starting dose for aripiprazole is 15 mg/day, once daily. Data demonstrate that 15 mg/day is effective and well-tolerated when administered from day one; 30 mg administered once daily has been established as an effective dose and is the highest dose systemically evaluated including trials. Aripiprazole also can be administered without regard to meals.Drug interaction studies in healthy volunteers to date have revealed the following increased plasma concentrations of aripiprazole: ketoconazole (inhibits CYP3A4) by 67%; quinidine (inhibits CYP2D6) by 100%; and carbamazepine (inducer of CYP3A4) by 70%.
ARIPIPRAZOLE SPONSOR TOUTS BENEFITS:
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 the 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 (Zyprexa) causes weight gain, ziprasidone (Geodon) increases the QTc interval and risperidone increases prolactin level. "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 symptopms of psychosis, such as delusions and hallucinations, by blocking D2 receptors, aripiprazole stabilizes or modulates them.
"The activity of aripiprazole varies, depending on the environment. If there is too little dopamine, there will be mild intrinsic activity," McQuade says.
He compares current atypical drugs to an "on-off switch," indicating that the drug blocks the dopamine D2 receptors, thus reducing the positive symptoms of psychosis such as delusions and hallucinations. However, the blocking action often reduces dopamine levels to the point where motor complications arise - i.e., EPS. "Aripiprazole acts more like a dimmer switch," says McQuade. "It's a modulator or stabilizer that goes to certain serotonin receptors."
McQuade underscores the multifacted 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 enahces 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-HT1A 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/day) in some studies. There is clearly a greater effect on the Barnes Akathisia Scale than from risperidone, and about the effect of haloperidol."
Erehefsky adds, "Akathisia is a potential side effect which bares further evaluation in long-term studies to see whether it abates."
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> I just read an article about a new anti-psychotic, aripiprazole, that is in a class of its own and claims to be a dopamine partial agonist, thus either increasing or decreasing dopamine levels as needed. It sounds too good to be true! I'm looking for a drug like this because I respond well to Mirapex and Dexedrine, but feel it would be best to find something to replace the dexedrine that might keep blood levels at a more steady state.
> Has anyone had any experience with this drug or know anything about it or been to any lectures about it with anectdotal info.?
>
> Chocoholic
poster:Sunnely
thread:95738
URL: http://www.dr-bob.org/babble/20020222/msgs/95753.html