By Stephanie Durruthy, MD
[Winter 2006; Vol. 33, No. 1; Pg 8, 12-13]
The
psychiatric community receives a wealth of information to better serve our
patients. Those versed in reproductive psychiatry can quickly reference
potential guidelines with an FDA advisory, a litany of published articles in the
coveted New England Journal of Medicine, and a series of eye catching headlines
in both the psychiatric and popular press. At first glance, this deluge of
information has given many clinicians a renewed sense of comfort in our world of
pharmacopoeia.
Unfortunately,
once our medical information is magnified under the microscope of scientific
scrutiny, there appears to be potential gaps in our knowledge. What follows is a
commentary about the state of reproductive psychiatry.
Can
the PDR be a guide for pregnancy medication counseling?
The
cornerstone of pregnancy counseling has been the PDR Pregnancy Label. Many
providers, with the Physician Desk Reference (PDR) as a guide, render confident
safety opinions
based upon the medication
designated categories of A, B, C, D and X.
However, psychiatrists often questioned the reliability of the PDR which
designated the Wellbutrin/Bupropion pregnancy label a category B. Few clinicians
would offer Bupropion/Wellbutrin as the first line agent with depression during
pregnancy despite its preferred designation.
The
Buproprion/Wellbutrin coveted B designation was based upon animal studies, while
the most popular SSRIs prescribed during pregnancy had a growing data base of
human outcomes putting them in category C. Years would pass with most of the
SSRIs losing
prized drug patents before the FDA finally changed the designation of
Bupropion/Wellbutrin
to a category C in 2006.
While
the PDR pregnancy label seemed simple and easy to understand, the FDA never
intended it to be used to dictate treatment.
Most pregnancies are not planned. The FDA labeling system does not
address “oops babies”.
This labeling system does not address the impact of limited medication
exposure in an unplanned pregnancy.
The information obtained to designate a category is often gathered from
animal not human data. Furthermore, most category designation updates are not
timely, as demonstrated by the Bupropion Pregnancy label(1).
The
FDA is in the process of revamping their pregnancy labeling system.
Unfortunately, this policy change will require years of bureaucratic wrangling
in order to obtain a new legislative agenda. Meanwhile, not all physicians are
aware of the PDR limitations for use during reproductive counseling.
Who
controls the toll booths on the pregnancy information highway?
The
perceived joy of motherhood permitted many clinicians to assume that pregnancy
could stabilize depressive illness. Yet Cohen L, et al. (2006) determined from
his longitudinal prospective study of depression among 201 females, 43% would
relapse during pregnancy.
Among women who maintained their medication during pregnancy, 26%
relapsed vs. 68% who discontinued their medications during pregnancy.
Surprisingly, the study noted that 61% of females who discontinued medications
eventually reintroduced antidepressants during pregnancy(2).
The
widespread media coverage of Cohen’s noteworthy contribution omitted crucial
unanswered questions. Minority participants were lost to follow up.
The study finding does not address women who are currently clinically
depressed without a prior episode of depression. Statistical analysis
identifying the risk of depressive relapse is associated with a history of
recurrence, but women who are older than 32 years old have a 60% reduction in
relapse rate. The potential bias of a non- randomized study was not highlighted
due to the ethical dilemma of withholding treatment.
Cohen’s
findings, in the midst of a persistent pulmonary hypertension report secondary
to late term SSRI”s pregnancy exposure, were the early controversies of
2006(3). One would assume that all the buzz about pregnancy and medication in
the media would be addressed at the usual industry supported symposium about
women’s health at the American Psychiatric Association Annual Meeting in
Toronto. Surprisingly, the extremely popular women’s health industry dinner
meeting was absent as were the
big
names in the reproductive health field.
It is a sad possibility that since most of the SSRIs have lost their
patents there is no need for pharmaceutical companies to educate. The Toronto
APA’s industry meetings seem to be dominated by lectures for insomnia,
treatment resistance, attention deficit disorder, and bipolar disorder which
support the latest pharma products. In my opinion, the benefit of the dinner
meetings was the off- label question and answer periods for cutting edge
discussions in reproductive psychiatry.
If
a psychiatrist does not obtain the latest agenda in reproductive psychiatry at
the annual meeting, where is the information readily available?
Medical abstracts are eye-catching and brief in nature prohibiting
methodology and design analysis. Published journal articles can be difficult and
costly to obtain. Medical libraries in academic centers are not readily
accessible or open to public domain. Psychiatric online databases do not include
all specialty journals. Fre-quently, pharmaceutical companies reference
copyright
laws which prevent them from disseminating original scientific papers.
Surprisingly, many pharmaceutical company business positions have
abruptly changed, and many are now unable to provide the review research papers
referenced on their “Dear Doctor” advisory letters. In our current
environment, how is timely medical information disseminated in reproductive
psychiatry to the health professions?
Can
physicians understand
the complexity of research design in reproductive psychiatry?
Unfortunately,
the Federal Drug Administration slide found on its website about Pregnancy
Labeling accurately describes the state of the research. It sadly summarizes
reproductive psychiatry as an “area of medicine where the most certainty is
desired, but there is the least data.” The ethics of randomized trials and the
potential risks of neonatal exposure have limited research findings.
Often
researchers extrapolate data bases from case reports through the use of Medline
and other psychiatric computerized information. Moises-Koklo et al scanned for
key words in their landmark study on adverse neonatal signs during late
trimester exposure of SSRIs, and this influenced the recent FDA Product Label
Advisory. They identified thirteen published articles that describe eighteen
cases of adverse neonatal signs(4).
The
difficulties of using computerized data bases with key words in case reports are
numerous. The findings are limited by their lack of standardized information
about maternal medical history, delivery complications, and infant medical
workup. Furthermore, health professionals tend to report severe complications of
drug exposure, not minor observations. Case reports are not able to determine
the all important incidence rate of adverse events (4).
On
the other hand, cohort studies are designed to determine the highest quality of
information regarding prenatal signs. Cohort design is a comparison between
women who had drug exposure during the first two trimesters but not the third.
This group is then compared to pregnant women exposed in the third trimester.
Sadly, pharmaceutical research methodology and design is very limited in
reproductive psychiatry.
How
is a busy clinician to understand the research data presented about reproductive
safety?
It is the exceptional clinical psychiatrist who has sound statistical
knowledge and medical statistics are generally not provided as a topic for
continuing medical information.
Life
Post Vioxx: Can the pharmaceutical companies police themselves?
The
psychiatric community received a bombshell last year with the Glaxo Smith Kline
disclosure that Paxil may cause potential cardiac deficit with neonatal
exposure.
Psychiatrists asked themselves what are the options for a very anxious,
depressed female who is pregnant? Many of us had no other choice but to return
to benzodiazepines.
The aftermath of uncertainty has fostered a rumor or reality that
psychiatrists no longer treat pregnant patients but refer to their
obstetricians.
Suddenly, the world of treatment for depressed pregnant females became
more complicated and too risky.
What
make Paxil so unique? Can other SSRIs be implicated with congenital deficits?
Many of us anxiously awaited the published study to review. Months passed by,
Paxil has a category D designation, and there is still no published study.
Why Paxil? Many would describe the paroxetine molecule as unique, having
the greatest affinity for the serotonin and muscarinic receptors of the SSRIs.
It has the shortest half life and lacks an active metabolite which increases its
associated adverse outcomes when it’s discontinued(5).
Unpublished
reports from a large data base of a health maintenance organization and a
Swedish Medical Registry cited a 1.5 to 2.0 fold increase in cardiovascular
disease with first trimester exposure to paroxetine.
The most common cardiovascular malformations among the paroxetine exposed
infants were ventricular septal defects(6).
Life
post Vioxx, dictates quickly disseminating any adverse side effect. Yet there is
no need for replication in an animal model, no mandates for further research and
maybe no published article for review.
It appears the Paxil data is proprietary. In my opinion, the Paxil
disclosure or lack thereof left the medical community in the dark.
Physicians learned nothing about their research process or how the
conclusions were determined. Did Glaxo Smith Kline’s disclosure aid the
medical community or was divulging the information just a risk management
business decision ?
In summary, we have been often told that the
greatness of a society can be determined by
its treatment of the elderly, children, and mentally ill. Who advocates
that medical
information disseminated for
the unborn children of our patients be accurate and up to date?
Stephanie
Durruthy has a private practice in Ellicott City.. She is the author of the
award winning book, The Pregnancy Decision
Handbook for Women with Depression Dr Durruthy is a member of the Women’s Committee of the
American Psychiatric Association.
References:
1 Kweder S.
“Labeling Products for Use in Pregnancy Moving Forward”(lecture
Psychopharmacology and
Reproductive Transitions:Impact of Psychotrophic Medications ans Sex Hormones on
Brain Functioning, Weight, and Reproductive Safety Symposium)American
Pyschiatric Annual Meeting, New York,NY May 2, 2004.
2 Cohen L.,Altshuler LL.,et
al. Relapse of Major Depressive During Pregnancy in Women Who Maintain or
Discontinue Antidepressant Treatment. JAMA 2006;295(5):499-507
3 Chamber CD.,Hernandez-Diaz
S., et al. Selective-Reuptake Inhibitors ans the Risk of Persistant Pulmonary
Hypertension of the Newborn. JAMA 2006;354(6):579-587
4 Moses-Kolko EL., Bogen D.,
et al. Neonatal Signs After Late in
Utero Exposure to Serotonin Reuptake Inhibitors. JAMA 2005; 293(19):2372-2383.
5 Sanz EJ, De La-Cuervas.,
et al. Selective Serotonin Reuptake Inhibitors in Pregnant Women and Neonatal
Withdrawal Syndrome: a Database Analysis. Lancet 2005; 365:482-87
6 http://www.gsk.com/media/par_current_analysis.htm assessed 7/23/06