--Demitri and Janice Papolos
If a parent and a doctor
were to dream up a wish list mood stabilizer for a child suffering with bipolar
disorder, it would be extremely effective without major side effects, it would
work against aggression and rage, it would prevent future episodes of illness,
it would require no systematic blood draws, and it would not cause weight gain,
liver toxicity or aplastic anemia.
An anticonvulsant launched
in this country a year ago February (but used in the pediatric epilepsy population
since 1990 in Europe), seems to hold a lot of these cards upon early examination,
but much is still left to be seen. It is called oxcarbazepine and is marketed
in this country by Novartis under the brand name, Trileptal.
Actually, Trileptal is an
analogue of Tegretol (carbamazepine). An analogue is structurally similar to
another compound, but differs slightly in its composition (such as replacing
one atom by another atom of a different element).
Someone in the Ciba-Geigy labs
in Switzerland, played around with the carbamazepine compound and added one oxygen
molecule to the top of the middle structure. What a difference an oxygen atom
can make: Whereas carbamazepine oxidizes in the body into an active metabolite
called 10,11 epoxide, oxcarbazepine rapidly converts in the body to 10-monohydroxide
derivative (MHD). (Please click here (http://www.bipolarchild.com/newsletters/metabolism_oxcarb.html)
to see a figure of the chemical structure and metabolism of oxcarbazepine vs.
carbamazepine.) Carbamazepine (Tegretol) is an effective mood stabilizer for bipolar
disorder, but it seems that the 10/11 epoxide metabolite is responsible for some
of the major problems that can occur with the drug.
As we write in The Bipolar
Child, "because Tegretol activates certain enzymes in the liver, and this
causes the drug itself and many others to be metabolized faster, the serum Tegretol
level may drop somewhat after the first month of treatment, requiring increased
doses based on blood levels." Therefore, blood levels are needed more frequently
in the beginning of treatment and every three months or so afterward. "(Anecdotally,
we have heard of many instances when blood levels have dropped--particularly
in young children--multiple times with successive increases in dose due to this
enzyme induction.)
This induction of the liver
enzymes is a result of the 10,11 epoxide metabolite. In contrast, the principal
metabolite of Trileptal's (MHD) has little effect on liver enzymes, so that
its own serum levels remain fairly constant. Moreover, unlike Tegretol, it is
less likely to increase the rate of elimination of many other drugs.
There have been several
reports of bone marrow suppression (aplastic anemia) with Tegretol. While very
rare, this is a life-threatening condition. Even less likely are suppression
of the formation of blood platelets required for forming blood clots, and white
blood cells that fight infection. Therefore, it is good medical practice to
have a complete blood cell count regularly at the beginning of treatment and
each time the patient develops any signs of easy bruising, and certainly if
the triad of fever, sore throat and rash develop in combination.
Evidently because of its
different metabolism, Trileptal is much less likely than Tegretol to cause aplastic
anemia. In addition, liver toxicity occurs rarely with Tegretol, but is unknown
with Trileptal.
Although Trileptal has less
risk of drug-to-drug interaction than Tegretol, it can increase the rate of
elimination, and reduce the effectiveness of some drugs--notably oral contraceptives
(parents of adolescents, please make note!) and one calcium channel blocker,
in particular, Felodipine. Therefore, Trileptal may be safely combined with
Lamictal, Depakote, and lithium, as well as with antidepressants and antipsychotic
medications.
Sounds great so far, but
you must be thinking: What are the side effects of Trileptal and how well does
it work?
The Side Effects
Adverse side effects that
may occur early in treatment with Trileptal are sleepiness (somnolence), headache,
dizziness, double vision, ataxia (unsteadiness), vomiting, rash, and abdominal
pain. Most of these side effects--should they occur--recede as the body adjusts
to the drug in a few weeks. We have heard of a case of sun sensitivity caused
by the drug (not surprising because Tegretol can cause this also).
There is a drop in sodium
levels (hyponatremia) in 3% of those taking Trileptal. Therefore, a baseline
lab test should be done on all patients before the drug is started, and children
with sodium levels below 135 mEq/L should be watched more closely. Hyponatremia
is rare in children, but teenagers who may ingest diuretics surreptitiously
for weight loss are at risk, and this should be explained to them at the beginning
of treatment.
Hyponatremia can be treated
easily and it is recommended as a general practice that every fourth drink should
be a sodium-containing one such as milk or Gatorade. Milk has 125 grams of sodium
in an 8-ounce glass, and Gatorade has 115 mg of sodium in an 8.45-ounce juice
box.
Symptoms of hyponatremia
include not passing much urine, headache, confusion, tiredness, and, if very
severe, seizure and coma. Because Trileptal has been shown to be very effective
in the treatment of partial seizures, it is FDA-approved as a monotherapy for
epilepsy in adults, and approved for children age 4 and older as an add-on anticonvulsant.
Therefore, we already have studies showing its safety in the pediatric population.
How Well Does Trileptal
Work in Bipolar Disorder?
Several studies have evaluated
the effectiveness of Trileptal in acute mania. In 1983, Dr. Hinderk M. Emrich
of the Max Planck Institute in Munich performed a double-blind, placebo-controlled
study using oxcarbazepine, and found an average change of 50% in the mania scales
was achieved by the use of this medication. As a consequence of these findings,
Ciba-Geigy of Basel organized two multi-center studies using oxcarbazepine.
One compared oxcarbazepine with the antipsychotic drug, haloperidol (Haldol).
After two weeks, both treatments (haloperidol and oxcarbazepine) were about
equally effective in the 58-patient study, on the basis of decreasing mania-scale
scores.
Another international study
compared the anti-manic effects of oxcarbazepine to lithium. Again, after a
two-week period, the drugs were found to have about equal efficacy for the treatment
of acute mania.
This past May, Michael Reinstein,
M.D., an Assistant Professor of Psychiatry at Rush Medical Center in Chicago,
presented a poster at the American Psychiatric Association's annual conference,
in which he compared Trileptal to Depakote in the treatment of mania and found
them to be indistinguishable in both efficacy and tolerability of side effects
in adults.
How well does Trileptal
work as a maintenance medication? To date, no drug but lithium has been approved
for the prevention of episodes of mania in bipolar disorder, and none is approved
for preventing recurrences of bipolar depression specifically. Nevertheless,
Tegretol and Depakote are used routinely for these purposes and often seem to
do the job well. We have only anecdotal information about prevention of episodes
and future stability with the use of Trileptal, but when we asked Dr. Reinstein
if he had noticed a preventative quality and how long he saw stability he answered:
"We have been using Trileptal a little over a year now and we are very
impressed with the stability we've seen in the patients. It has become the first
line of treatment in our clinic for our patients with bipolar disorder."
Dr. Reinstein also spoke of the effect Trileptal has on the aggressive behaviors
of the children he's seen. He said: "When the dose gets high enough, the
aggression tends to subside."
We next interviewed Dr.
Boris Rubinstein, an Assistant Clinical Professor of Psychiatry and Pediatrics
at Columbia University's College of Physicians and Surgeons in New York City
because he has treated a number of children with Trileptal. While he doesn't
yet use it as a first-line treatment, he told us he was impressed with its mood
stabilizing effects and--while cautious-- said that :"In my initial assessment,
I am very enthusiastic about Trileptal."
He feels that it may well
turn out to be a particularly useful drug for children and spoke of the difficult-to-assess
four-year-olds who present with ADHD and a lot of aggressive behaviors. "If
these are budding bipolar children, I would feel comfortable starting with Trileptal,"
he said. Unlike stimulants or antidepressants, this option would not exacerbate
a possible bipolar disorder.
Much remains to be learned
of Trileptal's efficacy in the treatment of early-onset bipolar disorder, and
whether or not it is an effective long-term maintenance treatment, preventing
future episodes of cycling. Studies are in the planning stages to answer these
questions. It is also important to emphasize that Trileptal is officially recognized
by the FDA as an anticonvulsant, and that all use in mania or to prevent recurrences
of bipolar disorder are to be considered empirical and "off-label,"
based on individual clinical decisions by a physician.
Dosing
Trileptal is supplied in
150, 300, and 600 mg tablets scored so that they can be cut in half. In addition,
there is a lemon-flavored oral suspension for children who have difficulty swallowing
tablets. The liquid preparation is palatable to children (we haven't tasted
it, however). It must be shaken well before given to a child. It is supplied
at a concentration of 60 mg/ml, or 300 mg per 5 ml teaspoon.
Children are typically started
at 300 mg per day--in divided doses--150 mg in the morning; 150 mg approximately
12 hours later. The manufacturer's recommendation is to raise the dosage every
7 days in increments of 300 mg (again the 300 mg increases are best divided
into two-a-day half- doses) with a target dose of approximately 900 mg to 1200
mg (some children may require as much as 1500-2400 mg).
The drug reaches a steady
state, or stable, concentration in the blood stream after about 4 doses or within
two days. One mother whose 11-year-old son was cycling wildly throughout the
day (despite his being on Clozaril and Zyprexa) wrote of her son's experience
with Trileptal: "At about three weeks, as his dose was 900 mg, we began
to see the amplitude of his mood swings diminish. At 6 weeks and 1200 mg, the
cycling practically stopped. Since no other medication was added at this time,
we're sure the Trileptal smoothed out the cycling pattern."
This young man has now been
on the medication for a few months and continues to do well, but--as we said
above-- only time will tell if the drug is effective as a long-term maintenance
mood stabilizer.
Serum Levels of the Major
Trileptal Metabolite (MHD)
A blood test is available
to monitor the serum level of MHD (monohydroxide derivative), but the clinical
value of this measurement is uncertain. At this point the blood test might be
useful to ensure that an adolescent is taking the medication--more of a measurement
of compliance, so to speak, whereas dosing is better guided by clinical response
and tolerability by individuals.
The Cost of the Medication
Trileptal is expensive--about
$1.50 for a 300 mg tablet, with only moderate increases in cost-per-pill for
larger quantities. If a child takes 1200 mg a day, then a one-month supply will
cost about $150-180. A 2400 mg per day regimen could cost nearly $300 a month.
As we wrote in The Bipolar
Child (page 128), "Everyone should comparison shop for medications. The
same medication in three drugstores in the same neighborhood can have three
very different prices. Also, purchase the largest-size tablet or capsule available,
consistent with the dosage prescribed." (A patient taking 1200 mg of Trileptal
would pay less for two 600 mg tablets than for four 300 mg tablets.
For families that don't
have prescription cards or funds to pay for Trileptal, Novartis runs a program
that will supply the medication for free. It can be applied to by the treating
physician.
In Conclusion
Naturally, we wish we could
give you more information about Trileptal, but we are hopeful that-- for some
children--this is a new ally in the fight against this dreadful illness. Because
Trileptal's safety profile in children is promising, its levels don't fluctuate
due to liver enzyme induction, it requires few blood draws, and it doesn't cause
the distress of weight gain, it is a welcome new tool in the psychiatric armamaterium;
another option on the table.
We also hope that Trileptal's
safety profile will help doctors feel more comfortable making the diagnosis
of early-onset bipolar disorder and treating the illness at an earlier age,
thus saving the child and the family the chaos this disorder engenders. Perhaps
fewer doctors will adopt a "wait-and-see" attitude because they fear
possible adverse effects from mood stabilizers.
However, we want to make
the point clearly that if your child is doing well on Tegretol, Depakote, lithium,
etc. it is unwise to change the regimen because you read about a new drug or
supplement. No one drug works for every child, and these other mood stabilizers
have known advantages (for instance, there is emerging evidence that lithium
has a strong and possibly unique effect against suicidal behavior and is neuroprotective
as well). If your child is stable, do nothing to rock that blessed boat.
*********************************************
Bibliography
Dunn, Robert T., Mark S. Frye et al. "The Efficacy and Use of Anticonvulsants
in Mood Disorders." Clinical Neuropharmacology 21 (4): 215-235.
Emrich, H.M., M. Dose, and
D. von Zerssen. "The Use of Sodium Valproate,
Carbamazepine and Oxcarbazepine in Patients with Affective Disorders."
Journal of Affective Disorders 8 (1985): 243-250.
Papolos, Demitri, and Janice
Papolos. The Bipolar Child. New York: Broadway
Books, 2000.
Reinstein, Michael J. John
G. Sonnenberg, Sangarapillia C. Mohan, Maxim A Chasanov et al. "Comparative
Efficacy and Tolerability of Oxcarbazepine versus
Divalproex Sodium in the Treatment of Mania." A Poster presented at
The American Psychiatric Association Conference, New Orleans, 20001
The authors wish to thank,
once again, Ross J. Baldessarini, M.D. for his abiding interest and expertise.
*********************************************
As a final note, we'd like to point out two non-Trileptal matters: For our Texas
readers who have asked when Demitri will be speaking in their state, save October
3rd and 4th, 2001. He will be speaking in Austin under the sponsorship of the
Austin Harvard School for two-full-day workshops. Since this is one of only
two schools in the country set up specifically to teach children with bipolar
disorder and ADHD, we will report on the school's philosophy and curriculum
in our next newsletter. (Find out all the details under "Workshops"
at http://www.bipolarchild.com. )
*********************************************
RESEARCH
SURVEY
We are conducting a survey having to do with carbohydrate craving and temperature
regulation in children diagnosed with bipolar disorder, and hope that you will
find the time to help us in this research effort. The questionnaires shouldn't
take more than 15 minutes to complete. In addition, we would ask you to measure
your child's body temperature with an oral mercury thermometer at 4 specified
times within a 36-hour period.
If interested, below, you
will find links to four separate RTF files:
-
Instructions for the study (http://www.bipolarchild.com/docs/instructions_for_study.rtf)
-
The
food cravings and thermoregulation survey with answer sheet, (http://www.bipolarchild.com/docs/food_cravings.rtf)
-
The
Bipolar Child Parent Questionnaire, (http://www.bipolarchild.com/survey/bipolar_chi_nnaire_v1_2.htm)
-
The
body temperature recording sheet. (http://www.bipolarchild.com/docs/body_temperature.rtf)
Each of these files has
instructions that will hopefully allow you to complete the survey without difficulty.
Please open (1) Instructions
for the study first. This document explains the steps that are required to complete
the survey.
As soon as the findings
are published in the psychiatric literature, we will discuss them in detail
in a future newsletter. Thank you so much for considering participating in this
study!
Because so many parents signed on after the launch of this newsletter, we'd
like to index previous editions. They can all be found under http://www.bipolarchild.com
if you click on "Info and Articles." To date, we've covered the following
topics:
Bipolar Disorder, Co-Occurring
Conditions, and the Need for Extreme Caution Before Initiating Drug Treatment
- November 1999
Millennium Issue: Aggression
and the Overarousal of the Limbic System in Children with Bipolar Disorder -
January 2,000
Mood Stabilizers: An Update
- March 2000
Night Terrors in Children
with Bipolar Disorder - July 2,000
Atypical Antipsychotics:
Should They Be Prescribed as a Monotherapy? - October2000
What Can the Amish Teach
Us About Early-Onset Bipolar Disorder? - January 2001
The A-Zs of Omega-3's: Essential
Fatty Acids in the Treatment of Bipolar Disorder - May 2001
