Do Not Use Until December 2009 The New Antipsychotic Drug Aripiprazole (ABILIFY)

The Food and Drug Administration (FDA) approved aripiprazole (ABILIFY) in December 2002 for the short-term treatment of schizophrenia. Aripiprazole is marketed by Bristol-Myers Squibb and Otsuka America Pharmaceutical, Inc., and brings to six the number of “atypical” antipsychotics now on the market.

This evaluation is based primarily on the publicly available FDA reviews of data submitted by Bristol-Myers Squibb/Otsuka to support the approval of aripiprazole. These reviews are essential in conducting an independent evaluation of the therapeutic value of a new drug. We can no longer totally rely on the peer-reviewed medical literature as the gold standard for the dissemination of scientifically valid information. One industry insider claims that 50 percent of the medical literature on drugs is ghostwritten with a positive spin. The editor of the Canadian Medical Association Journal recently said, “We have no way of checking. We barely have the resources to do what we’re doing, let alone whether so-and-so is telling us honestly what they did.”

The FDA reviews of aripiprazole can be found on the agency’s web site at www.fda.gov/cder/foi/nda/2002/21-436_Abilify.htm.

All antipsychotics tend to improve symptoms such as hallucinations, agitation, delusions, suspiciousness and disorganized thinking. The atypical antipsychotics better improve the negative symptoms of schizophrenia, such as apathy, emotional withdrawal, lack of pleasure and disorientation, than older antipsychotics. Haloperidol (HALDOL) and chlorpromazine (THORAZINE) are two examples of older, or typical, antipsychotics. The newer atypical antipsychotics may be less likely to cause adverse effects on equilibrium and muscle tone, often called movement disorders, at moderate doses. However, in higher doses, these medications can cause serious adverse effects, including elevations in blood sugar (hyperglycemia). See the July 2002 Worst Pills, Best Pills News article about drug-induced hyperglycemia with clozapine (CLOZARIL) and olanzapine (ZYPREXA).

We have a significant concern about the possibility of eye toxicity with the use of aripiprazole. The studies done in rats clearly showed degeneration of the retina in animals receiving aripiprazole. The studies done in mice and monkeys found no retinal degeneration but they were invalid studies. The company committed to doing additional post-marketing research on retinal degeneration in animals as a condition for the approval of aripiprazole. These are studies that clearly should have been completed before the drug was approved.

Unfortunately, the drug industry’s performance in meeting their post-marketing study commitments is not good (see Worst Pills, Best Pills News, June 2000). From 1990 through 1994, a total of 88 new drugs were approved in which a company had made at least one post-marketing study commitment. Only 13 percent (11 of the 88) were classified by the FDA as complete as of December 1999.

The only advice given in the professional product labeling, or package insert, about the retinal degeneration seen in rats is not very comforting: “The relevance of this finding to human risk is unknown.”

Various rating scales are used to test the efficacy of antipsychotic drugs. A brief description of these scales can be found below. In general, the standard for showing that a drug works (its efficacy) is that the average scores on the rating scales improve and that the difference between the averages for those patients receiving a new antipsychotic, for example, are statistically different from the group of patients receiving an inactive placebo or another previously approved drug for treating the same problem.

Five short-term clinical trials were submitted by Bristol-Myers Squibb/Otsuka to the FDA to support the approval of aripiprazole.

The first trial lasted only four weeks. Altogether, 103 patients with schizophrenia in acute relapse were randomized to aripiprazole, haloperidol or placebo. Two rating scales were used, the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Severity (CGI-S) scale. Explanations of these rating scales can be found at the end of this article. Aripiprazole demonstrated borderline statistical superiority over placebo on the CGS-S scale only. Haloperidol was superior to placebo on both the BPRS and CGS-S scales.

The second trial was also a four-week study. This trial involved 414 patients who were given either 15 milligrams or 30 milligrams of aripiprazole, haloperidol, or placebo per day. In this trial, three rating scales were used: the CGI-S and the total score and positive subscale of the Positive and Negative Syndrome Scale (PANSS). Both doses of aripiprazole were found to be statistically superior to placebo. However, there appeared to be no therapeutic advantage of the 30 milligram dose over the 15 milligram dose.

The next trial, again only four weeks in duration, included 404 patients. These patients received either 20 milligrams or 30 milligrams per day of aripiprazole, the atypical antipsychotic risperidone (RISPERDAL) or placebo. This study also used the CGI-S and the total score and positive subscale of the Positive and Negative Syndrome Scale (PANSS) to evaluate the efficacy of aripiprazole. Both doses of aripiprazole were found to be better than the placebo. Risperidone was also found to be statistically superior compared to placebo on the three rating scales.

In the fourth trial, a total of 420 patients were assigned to receive either 10, 15 or 20 milligrams per day of aripiprazole or placebo. This was the longest of the five trials, but lasted only six weeks. The main rating scale used in this trial was the PANSS total score. The three different doses of aripiprazole were found to be superior to placebo. There was no clear advantage of the 15 milligram and 20 milligram doses over the 10 milligram dose.

The last trial studied 307 patients given aripiprazole, haloperidol or placebo. Neither aripiprazole nor haloperidol demonstrated superiority over placebo. This is known as a failed trial.

In summary, three of the five short-term trials lasting four or six weeks showed the efficacy of aripiprazole in doses ranging from 10 milligrams to 30 milligrams per day. There appeared to be no therapeutic advantage of the 30 milligram dose over the lower doses. The FDA-approved dose for the drug ranges from 10 milligrams to 15 milligrams per day. Of the two remaining studies, aripiprazole could not be differentiated from placebo in one, and the other trial failed.

These trials were not conducted in a way to make direct comparisons between aripiprazole and haloperidol or respiridone. And nothing in these five trials can lead one to believe that aripiprazole is a meaningful advancement in the treatment of schizophrenia.

There are additional findings from the FDA’s safety review of aripiprazole that are important. An alteration in the electrical conduction of the heart known as QT prolongation is an important safety issue with both old and new antipsychotic drugs. QT prolongation can lead to life-threatening heart rhythm disturbance. See the previous Worst Pills, Best Pills News articles about the Do Not Use drugs ziprasidone (GEODON) in the June 2001 issue and thioridazine (MELLARIL) in the September 2000 issue.

There was no evidence of QT prolongation with aripiprazole at doses up to 30 milligrams per day. However, in a special study that explored doses of the drug up to 90 milligrams per day, there was substantial prolongation of the QT interval at doses of 75 milligrams and 90 milligrams per day.

Again, the FDA-approved dose of this drug ranges from 10 milligrams to 15 milligrams per day, but there is nothing to prevent a physician from prescribing the drug in a much higher dose except the knowledge of the patient. Undoubtedly, many physicians will. The FDA is allowing Bristol-Myers Squibb/Otsuka to sell aripiprazole in 10 milligram, 15 milligram, 20 milligram and 30 milligram tablets. Generally, as a drug’s dose increases, so does the risk of adverse drug reactions.

In the short-term trials discussed above, drowsiness occurred in 15.3 percent of the patients treated with 30 milligrams of aripiprazole per day. Involuntary movement disorders are always a concern with antipsychotic drugs. The incidence of extrapyramidal symptoms in these trials were similar to placebo except for akathisia, a syndrome characterized by an inability to remain in a sitting position, with restlessness and a feeling of muscular quivering. Akathisia occurred in 10 percent of the aripiprazole treated patients compared to 6.8 percent of those receiving placebo.

A drop in blood pressure on standing (orthostatic hypotension) was seen in 14 percent of the patients receiving aripiprazole compared to 11.9 percent of those getting placebo. This can present a risk for falls.

Weight gain has also been a problem with the antipsychotic drugs, particularly with the atypical anti-psychotics. In the short-term trials, there was a small difference in average weight gain between aripiprazole and placebo patients. The patients given aripiprazole gained on average 1.5 pounds while the placebo patients lost 0.1 pounds on average. The proportion of patients gaining more than seven percent of their body weight who were taking aripiprazole was eight percent, compared to three percent of the placebo patients.

There are a number of potentially important drug interactions with aripiprazole. Because the primary effect of aripiprazole is on the central nervous system (CNS), patients should avoid alcohol and use caution if they are taking other drugs that affect the CNS. Aripiprazole also has the potential to enhance the effect of some high blood pressure-lowering drugs.

Carbamazepine (TEGRETOL) can induce the liver enzyme that is responsible for the breakdown (metabolism) of aripiprazole. This may result in faster elimination of the drug and a lower therapeutic effect.

Ketoconazole (NIZORAL), quinidine (DURAQUIN, QUINAGLUTE DURA-TABS, QUNIDEX), fluoxetine (PROZAC) or paroxetine (PAXIL) can inhibit the liver enzymes that breakdown aripiprazole. This can lead to higher blood levels of the drug and greater risk of adverse drug reactions.

The editors of the highly respected Medical Letter on Drugs and Therapeutics concluded in their February 13, 2003 evaluation of aripiprazole that “published comparisons with other atypical antipsychotics are needed to determine its relative efficacy and safety.”

The lack of comparative studies with other antipsychotics is sufficient reason to wait at least seven years before using this drug.

What You Can Do

You should follow the Health Research Group’s Seven Year Rule with aripiprazole. There is no evidence to suggest that aripiprazole is a “breakthrough” drug.