ABILIFY

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From Public Citizen

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 article on 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. 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 at the end this article. 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 previous articles on Ziprasidone (GEODON) AND Thioridazine (MELLARIL).)

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 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 effect the CNS. Aripiprazole also has the potential to enhance the

effect of some high blood pressure-lowering drugs.

Carbamazepine (TEGRETOL), a drug used frequently in combination with

antipsychotic medications, 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 before using this drug.

What You Can Do

You should follow the Health Research Group's Seven Year Rule with aripiprazole

and wait to use this drug as there is no evidence to suggest that it is a

" breakthrough " drug.

RATING SCALES USED TO ASSESS THE EFFICACY OF ARIPIPRAZOLE

Brief Psychiatric Rating Scale (BPRS): This scale consists of 18 items

with the total score representing the sum of all 18 items while the core items

score is the sum of 4 items (conceptual disorganization, suspiciousness,

hallucinatory behavior and unusual thought content). A decrease in BPRS score

reflects an improvement in the evaluated items in schizophrenic patients.

Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I):

evaluation is a single rating of how mentally ill a skilled rater feels the

subject is at the time of evaluation. A decrease in CGI-S score reflects

symptomatic improvement in schizophrenic patients. The CGI-I evaluation is a

single item reflecting a subject's improvement at baseline compared with

screening and improvement at each visit compared with baseline. An increase in

CGI-I score reflects symptomatic improvement in schizophrenic patients.

Positive and Negative Syndrome Scale (PANSS): This scale consists of 30

items, with the total score consisting of the sum of the seven positive items,

seven negative items and 16 general psychopathology items. The PANSS negative

subscale score is the sum of the 7 negative items. A decrease in PANSS score

(total, positive or negative) reflects improvement in the evaluated items in

schizophrenic patients.

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Posted 4/03