--Janice Papolos and Demitri F. Papolos, M.D.
Three years ago, we published the
first issue of The Bipolar Child Newsletter, and in the opening paragraph
we outlined what we hoped to accomplish: We wrote: "We thought an e-mail
newsletter would be a good forum in which to keep parents, educators, and mental
health professionals abreast of the newest findings in the fields of psychopharmacology,
genetics, and neurobiology as they relate to early-onset bipolar disorder.";
In keeping with that aim we'd
like to focus this issue on a newly available, novel, antipsychotic medicine,
aripiprazole (ari-PIP-prazole; brand name Abilify). Psychiatrists are starting
to prescribe it, parents are writing to us asking for information about it,
and early, anecdotal reports are promising. Much remains to be learned about
this unusual new drug. Very little is known about its potential clinical utility
and relative tolerability in children suffering with early-onset bipolar disorder,
and scientific studies of that application are only now beginning. Still, the
drug's unique properties and apparently excellent tolerability in adults
offer a great deal of hope.
Let us spell out what we know about
Abilify in February 2003.
Aripiprazole was discovered in Japan
by Otsuka Phramaceutical Co., Ltd. The compound entered Phase II trials for
patients with schizophrenia in that country by 1995, followed by Phase III trials
in Europe by 2000. In 1999, Otsuka-America arranged with Bristol-Myers Squibb
to manage Phase III clinical trials and marketing of the new drug in the US.
Abilify received FDA approval in November of 2002. It is so new that clinical
experience with it, particularly in children, remains very limited.
The Mechanism of Action
Aripiprazole is chemically different from other atypical antipsychotic agents
and is also believed to have unique pharmacological actions that are different
from other atypical antipsychotic drugs, including clopazine (Clozaril), olanzapine
(Zypexa), or quetiapine (Seroquel), risperidone (Risperdal), or ziprasidone
(Geodon). Aripiprazole acts as a weak stimulator (so-called "partial";
agonist) at dopamine D2 receptors, with the potential for exerting
either antagonistic (inhibitory) or agonistic (stimulating) effects, depending
on the sensitivity of the receptors and availability of dopamine, its natural
agonist in the brain. Aripiprazole also has similar actions at serotonin 5-HT1A receptors, as well as acting as an antagonist at serotonin 5-HT2A receptors, and having a number of other lesser actions.
In simple terms, partial agonism
refers to the ability of a drug to block a receptor if it is overstimulated
or in competition with a natural agonist, such as dopamine and serotonin themselves,
but also to stimulate a receptor when the natural agonist is unavailable. These
unprecedented properties in a clinically effective antipsychotic agent indicate
that Abilify can be considered a "next-generation"; atypical antipsychotic.
Aripiprazole is the first dopamine
partial-agonist approved in the US for clinical use in adult patients with schizophrenia,
although other dopamine partial-agonsists (e.g., bromocriptine [Parlodel] and
pramipexole [Mirapex]) have been used to treat Parkinson's disease for
many years. Aripiprazole is effective in reducing both the positive and negative
symptoms of schizophrenia, and is well tolerated by most patients. In addition,
promising research studies have been conducted with adults suffering with bipolar
disorder. A multi-center, double-blind randomized, placebo-controlled trial
included 262 adult patients diagnosed with acute mania or mixed manic-depressive
states. By day four of treatment, aripiprazole was significantly better than
placebo in reducing acute manic symptoms, including elevated mood, irritability,
disturbed thinking, and disruptive-aggressive behavior.
These findings have prompted adult
and child psychiatrists to begin to prescribe Abilify for both indicated and
off-label applications, including for early-onset bipolar disorder in children
and adolescents.
Advantages of Abilify
Like other atypical antipsychotics, aripiprazole has a low risk of producing
extrapyramidal symptoms (EPS)—the disorders of posture and movement that
some patients experience with the older neuroleptic-type antipsychotics, such
as chlorpromazine (Thorazine) and haloperidal (Haldol). Typical EPS include
early and later muscle contractions (dystonia), slowed movements (akinesia,
or parkinsonism), motor restlessness often accompanied by severe anxiety (akathisia),
and later-emerging tardive dyskinesia (TD).
In our newsletter of Fall 2000,
we first sounded some concerns about a series of general medical or metabolic
problems that were being increasingly reported in association with the atypical
antipsychotic medications such as Clozaril, Zyprexa, Risperdal, and Seroquel.
These include new-onset, type II (non-insulin dependent) diabetes mellitus,
changes in lipid metabolism and blood concentrations, sometimes severe and persistent
elevation of prolactin and other hormonal imbalances (milk oozes from children's
nipples), and a range of adverse cardiovascular effects that include low blood
pressure and abnormal functioning of the heart. The long-term implications of
such adverse effects are not known, particularly for youngsters who may require
such medications for decades.
Studies conducted with Abilify show
that patients gain little if any weight; and the drug seems to cause no changes
in the plasma glucose levels that might suggest risk of diabetes. Nor does it
seem to increase serum cholesterol or other lipids. Also, the drug does not
increase prolactin levels, and in fact appears to decrease them to normal levels,
and there have been no reports of heart rhythm abnormalities (such as a prolonging
of the electrical recovery time of the heart [QTc interval] in the electrocardiogram),
hematological changes, serum chemistry changes, or thyroid problems.
Parents who wrote to us asked if
there were any cases of tardive dyskinesia (TD), the late appearing movement
disorder that can present with involuntary facial grimacing, lip-smacking, chewing
and sucking movements, cheek puffing, and worm-like movements of the tongue,
as well as quick movements of the fingers, toes, arms and legs, or dystonic,
writhing postures. At this point there have been no reports, but it will be
years before anyone can answer this question with any authority.
The other question we were asked
was: "Does this med punk out like some of the others and will the doctor
have to keep increasing the dose?"; Again, we have few answers, but the
clinical trials involving patients with schizophrenia showed that Abilify sustained
improvements in the positive, negative, and depressive symptoms of schizophrenia
for at least a year.
The drug has been evaluated for
safety in at least 5,592 adult patients who participated in multiple-dose, premarketing
trials in schizophrenia, bipolar mania, and dementia of the Alzheimer's
type, for a total of approximately 3,639 patient-years of exposure. A total
of 1,887 aripiprazole-treated patients were treated for at least six months,
and 1,251 for at least a year.
Promising--so far, but what are
the side effects and how effective is it for children struggling with the symptoms
of bipolar disorder?
The Side Effects
The most common adverse effects reported among adult bipolar disorder patients,
specifically, included headache (32%), nausea (14%), vomiting (12%), constipation
(10%), anxiety (25%), insomnia (24%), dizziness (11%), and akathisia (10%).
Sleepiness was found with higher doses. Placebo-treated patients in the same
study also suffered side effects such as headache, agitation, nausea, indigestion,
and anxiety. Few of the side effects for either group lasted beyond the first
week.
Although many patients report few
side effects with the medication, in children, specifically, we have heard of
single cases: one very young child was taken off the drug due to severe constipation,
one 12-year-old had new mania, and one youngster had a dystonic reaction—one
of the movement disorders we spoke of above (dystonic reactions can be quickly
counteracted by antihistamines such as diphenhydramine [Benadryl], or by anticholinergic
drugs such as benztropine [Cogentin] or trihexyphenidyl [Artane]).
Dr. Raymond Behr, a highly respected
child psychiatrist on the faculty of the Albert Einstein College of Medicine
and founder of the Child Psychopharmacology Listserv for child psychiatrists
is very impressed with Abilify, but has reported five cases of akathisia (out
of the first 34 patients for whom he has prescribed the medication). He explained
that this was not "agitation,"; but "real akathisia.";
While the risk of EPS is much lower than with the older neuroleptic agents,
akathisia probably has a different basis than other movement disorders associated
with antipsychotic drugs, and can occur occasionally even with atypical agents.
Parents should be aware of akathisia and be alert to it.
According to Ross J. Baldessarini,
M.D. of Harvard Medical School, and one of the leading authorities on antipsychotic
medications:
Akathisia is motor restlessness
that can occur with all antipsychotics, typical or atypical, but is more likely
to occur with the older typical agents and D2 blocking agents. It can occur
occasionally and in subtle fashion even with clozapine. Akathisia involves
extreme subjective distress with a kind of "anxiety"; that involves
a physical sense of discomfort, often referred to the legs, and partially
relieved by moving around, hence the restless component. Sometimes it can
be treated with propranolol (Inderal) or benzodiazepines, but it may require
removing the offending agent.
He added: "This common condition
is often overlooked or misunderstood or mislabled as ‘agitation'
and it has been associated with aggressive or even suicidal behavior.";
Since so many children with bipolar
disorder suffer paradoxical reactions to all drugs (even those thought to quell
mania) the hypothetical risk of inducing or worsening mania or psychosis by
a dopamine partial-agonist still remains a concern for us and many clinicians,
and its clarification awaits more clinical experience.
Reports from the Medical
Front
Dr. Raymond Behr told us that "I have used Abilify in several kids and
many of the responses have been dramatically positive. My impression is that,
if it is going to work, there usually is a very quick response --within a few
days. It is very similar to the effect that one sees with Zyprexa (olanzapine)
but without the sedation and weight gain.";
We corresponded extensively with
Mani N. Pavuluri, M.D. the director of the Pediatric Mood Disorders Clinic at
the Institute of Juvenile Research at the University of Illinois at Chicago.
In one e-mail, she told us of a five- year-old child with bipolar disorder who
was severely psychotic, suffering delusions of reference, raging, and refractory
to three previous trials of mood stabilizers and two antipsychotics. The child
is now doing well on 5 mg of Abilify a day. (A four-year-old patient, however,
could not tolerate the drug due to constipation.)
Because Dr. Pavuluri and her colleagues
were so impressed with their observations of the effects of aripiprazole in
difficult-to-treat children who have bipolar disorder (and the results of the
five clinical trials that were completed at their center in adults) they have
designed a research protocol that proposes to examine Abilify in 7-17 year-olds
with bipolar disorder over a six-week period.
David Cremer, M.D. a psychiatrist
from Miami, Florida informed his collegues on the Professional Listserv of the
Juvenile Bipolar Research Foundation: "I have two young patients who are
bipolar and who have been on every medication for therapeutic trials and were
refractory, or who stopped medications due to side effects, and they are both
doing well on Abilify.";
When we contacted him and asked
for some more details, he described one of his children thus:
The first patient, KM, is seven-years-old
and his core symptoms were rages, sleeplessness, irritability with remorse,
low frustration tolerance, fickle changes in mood, rapid speech, and an ADHD
profile.
He was refractory to every medication
(all the anticonvulsants), he was briefly responsive to the atypical antipsychotics
and briefly responsive to lithium. On Abilify he has been able to engage in
play in the office and used the time to discuss some of his feelings about how
he has been feeling. The ADHD-type picture has abated with the medication.
Dr. Cremer then wrote about his
other patient, a nine-and-a-half-year-old boy:
TF has severe separation anxiety,
fickle moods, bursts of hyperactivity, some bizarre behavior, moodiness, and
spells of rages with pressured speech. He has responded to an atypical antipsychotic,
but with the side effects of puffiness and weight gain. He is on carbamazepine
without side effects.
Since starting him on Abilify,
he lost his puffiness almost immediately and is losing weight. His temper
has stabilized. He still has his moments, but they are within the realm of
average for his social delay.
Dr. Cremer mentioned that both of
these children showed improvement on their mental status exams.
Reports from the Home Front
How are the children doing on Abilify—at home and in school? Several parents
wrote to us and again, the stories were positive (but please bear in mind that
the negative stories have not reached us yet, and that all children will not
have these superb reactions or be able to tolerate the drug). One mother said:
Since Peter started the drug,
things have been so much better. He is on 10mg and the first few days he was
in a major "fog"; and slept a lot, and had an upset tummy. I thought
we were going to have to lower the dose but waited it out and things did get
better and the sleepiness went away and he no longer walks around in a fog.
Things are starting to "click"; in his head as far as school work
is concerned. His upsets are not rages anymore. And the constant fighting
with siblings......well, now it is just regular sibling rivalry that we have
never gotten to see before. He is much more compliant and his aggression level
has gone way, way down. He gets up in the morning and says: "Good morning";
instead of "I hate you!"; Not sure how long it will last, but I
am enjoying it very much!
She added something that reminded
us once again what this illness does not only to the child, but to the entire
family, and especially the siblings: She said: "His little brother is
still having a hard time understanding why Peter is being nice and not his usual
self that he was used to. But we are working on that.";
We've been corresponding with
the grandfather of a young boy for some time now and he wrote recently to tell
us of his grandson's reactions to Abilify. He said:
His daily reports from school
are all positive, and both his special-ed teachers are now able to concentrate
on his education instead of his behavior. I notice there is no more cycling
and no more rages. He is more calm; and when things go wrong, he doesn't
explode as he did in the past. As a result of the Abilify, he is a happier
9-year old, and I no longer walk on egg shells when he is with me.
Another mother described her fourth-grader's
reaction to the medication thus:
He began the Abilify and on the
third to fourth day, we saw dramatic improvement. It was almost as if we were
dealing with a different child. The rages stopped. He has always been an affectionate
child, but now his affection shines through clearly. He's been getting wonderful
reports from his special- ed teachers at school. I still find myself preparing
for battle when I have to reprimand him, but I'm pleasantly surprised when
he complies with my requests now and there is no problem. This medication
has been truly amazing for my son and our family.
And because there is no such thing
as too much good news to parents of children suffering with bipolar disorder,
we conclude with this mother's description:
While it hasn't solved all
of our son's problems, it has controlled his paranoia and mania, decreased
his grandiosity (but not eliminated it), made it possible for him to read
and focus better, and has done all of this without major side effects (once
we got up to 15 mg and eliminated the other antipsychotic medications completely).
He tells me that he feels much better able to control himself. He says that
he can now read without his mind wandering off in different directions. He
can also let negative issues drop, rather than dwelling on them.
She continued:
We have noticed a big change in
him. He gets up in the morning and stays awake and alert all day (no sedation).
He is generally more cooperative and although he still does annoying things,
I can now confront him without feeling like I need the National Guard to back
me up. His pediatrician, his therapist, and teachers at school have all noticed
the change for the better.
There is something intriguing in
this story and in Dr. Cremer's reports above. The children's focus
and attention seem to have improved on Abilify. Indeed, Dr. Mani Pavuluri proposes
to look at the drug's ability to improve cognitive functioning in her
study patients. The results should be interesting for all in the field, and
for all parents and educators.
Dosing
Abilify is supplied in 10, 15, 20, and 30 mg tablets--a disadvantage for children,
who are typically started on lower doses. Parents can cut tablets into halves
or even quarters, or bear extra costs in using the services of compounding pharmacies.
We understand from Bristol-Myers Squibb that lower milligram formulations as
well as a liquid formulation will be available some time "in the foreseeable
future,"; but we can't be any more specific than that.
Typical adult doses for the treatment
of psychotic disorders are 10-15 mg/day, with an overall range of 5-30 mg. Doses
for children are not established yet, but are likely to be about half those
used for adults. Moreover, the specific use of this drug to treat psychotic
patients under age 18, or for those diagnosed with bipolar disorder is not approved
by the FDA, though it is evidently starting to be used clinically on an off-label
basis in adolescents and children and for bipolar disorder patients.
Dr. Pavuluri reports that she starts
youngsters weighing less than 110 pounds at 2.5 mg, and those over 110 pounds
at 5 mg initially to avoid nausea, and doubles the dose within a week if it
is tolerated. Further dose increases usually are not made for another week or
two as steady state, or stable, tissue concentrations are achieved.
It is a good idea to give the medication
in the morning, with a meal or some food in order to minimize risk of nausea
and insomnia, which are among its most common side effects. Also, parents should
ensure that the child eats fruit and vegetables, or high-fiber cereals, and
drinks plenty of fluids in order to prevent constipation.
Drug-to-Drug Interactions
The anticonvulsant mood stabilizer, carbamazepine (Tegretol), induces CYP3A4
and 2D6 liver enzymes which can increase the ability of the body to
remove Abilify, and so decrease Abilify's concentration in the
blood. The manufacturer recommends that the dosage of Abilify be doubled as
long as both drugs are taken at the same time. This consideration brings up
the question as to whether Trileptal (oxcarbazepine, an analogue of carbamazepine)
can cause this same increase in clearance as Trileptal also has some effect
on the liver enzyme CYP3A4 that normally removes Abilify. The possibility seems
to exist, but no one has a definitive answer about this yet and careful dosing
ad an attentive eye to the clinical picture will be required.
Antidepressants such as fluoxetine
(Prozac) fluvoxamine (Luvox) and paroxetine (Paxil) can slow the body's
ability to eliminate Abilify by inhibiting CYP3A4 and CYP2D6 liver enzymes,
and so increasing blood levels of the drug. When any of these SSRIs are prescribed
with Abilify, the manufacturer recommends that the Abilify be reduced at least
to one-half of its current or usual dose.
Again, physicians who have patients
on either class of these medications will have to monitor the clinical picture
carefully and make adjustments as needed.
The Cost of the Medication
Abilify is very expensive. A Connecticut retail pharmacy quoted the following
prices for 30 tablets at each of three dosages: 10-mg or 15-mg, $357, and 20-mg,
$506. (We have seen cheaper prices so it behooves all parents to shop around.)
For families who don't have
prescription cards or the funds to pay for Abilify, Bristol-Myers Squibb moved
quickly to set up a Patient Assistance Program at 1-800-332-2056.
Conclusions
Because early anecdotal reports from researchers, clinicians, and parents seem
so positive, and because the drug's safety profile has been very promising
to date (and it doesn't confound a child's problems with weight
gain), it is hard not to be hopeful about this new medicine. However, it is
important to state again that Abilify is only beginning to be studied in children,
and a more balanced picture is certain to evolve as data accumulates. (A study
is currently enrolling at the NIMH comparing risperidone to aripiprazole in
youngsters aged 8-18 years, with psychotic symptoms who have responded unsatisfactorily
to at least one other adequate trial of an antipsychotic. To read more about
this study and to see if your child qualifies, go to http://www.ClinicalTrials.gov and type in aripiprazole.
We are forever walking a fine line
between that all-important emotion called hope, and a need to stay open-minded
and await the data. One of the mothers we quoted above, put it so wisely when
she wrote:
Although this medication has been
wonderful for my son, I would not want to raise hopes for other bipolar parents
by singing its praises too much. I know how it felt when I heard wonderful
things, hopeful things, about other medications that were found to be effective
with bipolar disorder. As the parent of a bipolar child, when getting overly
hopeful about a medication and then going through the painful and frustrating
experience of trying it only to find it did not work (or worse--it exacerbated
the symptoms of the bipolar disorder), it was heartbreaking. I guess with
all the variations in brain chemistries unique to individuals with bipolar
disorder (or any other psychiatric illness), there can't be one medication, the medication, that cures bipolar disorder. I think all parents need
to be reminded of this so they're not setting themselves up for a fall
We've said it before, and
it bears repeating again: If your child is doing well on his or her present
medications, it is unwise to change the regimen because you read about a new
drug--here or anywhere. If your child is stable, do nothing to rock that blessed
boat.
We will continue to gather information
about Abilify and its effect on children suffering with bipolar disorder, both
on the research and the clinical fronts, and we would appreciate hearing from
any of you whose children have had experience with it.
At this time of mid-winter and always,
we wish you and your children the best,
Janice Papolos and Demitri F. Papolos, M.D.
Bibliography
Baldessarini, R.J. E-mail correspondence of February 5, 6, and 10, 2003.
Behr, Raymond. E-mail correspondence
of February 4, 2003. Telephone Conversation Of February 10, 2003.
Burris, KD, Molski TF, et al. Aripiprazole,
A novel antipsychotic is a high-affinity partial agonist at human dopamine D2
receptors. Journal of Pharmacological Exp Ther 2002;302-389.
Goodnick, PJ, and Jerry, JM. Aripiprazole:
Profile on efficacy and safety. Expert Opinion Pharmacotherapy 2002; 12: 1773-1781.
Jody, Darlene, Ronald Marcus, Paul
Keck, et al. "Aripiprazole vs. placebo in acute mania. (poster), Proc
Am Psychiatr Assoc Annual Meeting, May 2002.
McGavin JK, Goa KL. Aripiprazole.
CNS Drugs 2002; 16: 779-786.
Papolos, DF. and Papolos J. The
Bipolar Child, Revised Edition. New York: Broadway Books, 2002.
Papolos, J and DF. Papolos. The
Bipolar Child Newsletters Volumes 5 and 10. (www.bipolarchild.com)
Pavuluri, MN. E-mail correspondence
of Feburary 3 and 4, 2003.
The authors would like to thank
Mani N. Pavuluri, M.D., Raymond Behr, M.D., David Cremer, M.D., Robert McQuade,
Ph.D., Mort Fineberg, Mary Fineberg, Catherine Schwartz, Niki Tenn, and especially,
Deborah Storms, for their contributions to this newsletter. For his abiding
interest, wisdom, and friendship, as well as his specific help with this report,
we acknowledge Ross J. Baldessarini, M.D.
www.bipolarchild.com
