Selective serotonin reuptake inhibitors and congenital malformations
BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b3525 (Published 23 September 2009) Cite this as: BMJ 2009;339:b3525
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I wholeheartedly agree with Dr.EL-Adl's comment regarding the need
for larger
more definitive studies that are conducted using sound methodology and in
a
timely fashion. This is not just true for SSRIs, but for all medications
likely to be
used by women of childbearing potential. Systematic and rigorous post-
marketing studies of human pregnancy with the most appropriate study
designs
should be the standard. Although getting to clear-cut answers, especially
regarding low risks, and when we usually cannot conduct clinical trials in
pregnancy, is challenging, it is nevertheless in my opinion, worth the
effort.
Competing interests:
see list of sources of grant funding
in the original editorial
Competing interests: No competing interests
I appreciate Dr. Fox's response to this editorial, highlighting an
important
component of the pregnancy treatment guidelines recently released by the
American Psychiatric Association and the American College of Obstetrics
and
Gynecology regarding treatment of depression in pregnancy. As noted in
this
editorial, the guidelines state that psychotherapy can be considered as a
viable
alternative to treatment with antidepressants in women who are or who are
planning to become pregnant. As stated in the guidelines, and reiterated
in the
editorial, the mention of consideration of psychiatric history presumably
refers
to situations in which therapy alone has previously proven ineffective or
there
are other compelling clinical indications for medication.
Competing interests:
See listed sources of grant funding
in published editorial
Competing interests: No competing interests
In 1991 in the
week FDA held regulatory hearings on Prozac and suicide, the BMJ published
an article by Lilly employees exonerating Prozac of blame even though
there was a clear increase in risk on treatment in the published article
and the article included under the heading of placebo a suicide that had
not happened in the randomized phase of the trials (1)(2). This likely
played a part in the way academics worldwide viewed the issues. Since
then in my experience in the run up to major legal trials or regulatory
hearings linked to SSRIs, one or other major journal has run an article
exonerating the drug(s). (I have no idea if something similar can be
linked to legal or regulatory issues involving other pharmaceuticals such
as Vioxx).
This week’s BMJ has an article on birth defects and SSRIs which
points to a risk on treatment (3). It is accompanied by an editorial
minimising those risks by Dr Chambers who has co-authored other pieces
advocating the treatment of antenatal depression with antidepressants (4).
Intriguingly Dr Chambers is in possession of a dataset pointing to
statistically significant 5.1 fold increased odds ratio of major birth
defects and a 10.8 fold increased odds ratio of cardiac defects on Paxil
but these data remain unpublished in the peer-reviewed literature almost
10 years after they were first generated (5).
This week GlaxoSmithKline open their defence in the first Paxil
linked birth defect case to go to trial. What odds their lead counsel
will brandish a copy of the BMJ in front of jurors? I have no reason to
think any member of the editorial staff of BMJ have been complicit in any
wrongdoing but there does seem to be something here worthy of further
investigation. Dr Chambers’ argument is that the risks of non-treatment
outweigh the risks of treatment – despite a doubling of the risk of
miscarriage. But do the risks of publication of this editorial outweigh
the risks of non-publication? Is there in other words a need for some SPAM
filter here?
References
1. Healy D. Did regulators fail over selective serotonin reuptake inhibitors?
BMJ Jul 2006; 333: 92 - 95.
2. Beasley CM, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH, Heiligenstein JH. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. BMJ 1991;303: 685-92.
3. Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH.
Selective serotonin reupake inhibitors in pregnancy and congenital
malformations: population based cohort study. BMJ 2009;339:b3569
doi:10.1136/bmj.b.3569
4. Chambers C. Selective serotonin reuptake inhibitors and
congenital malformations. The small risk of harm must be balanced against
risk of suboptimal or no treatment. BMJ 2009; 339: b3525
doi:10.1136/bmj.b3525.
5. www.gsk-clinicalstudyregister.com/files/pdf/24089.pdf
Competing interests:
DH is a witness for the plaintiff in the legal case mentioned in this letter. In the past 10 years DH has had consultancies with, been a principal investigator or clinical trialist for, been a chairman or speaker at international symposia for or been in receipt of support to attend meetings from: Astra-Zeneca, Boots/Knoll Pharmaceuticals, Eli Lilly, Janssen-Cilag, Lorex- Synthelabo, Lundbeck, Organon, Pharmacia & Upjohn, Pierre- Fabre, Pfizer, Rhone-Poulenc, Roche, Sanofi, GlaxoSmithKline, Solvay In the past two years, DH has had lecture fees and support to attend meetings from Astra- Zeneca and Lundbeck. In the past ten years DH has been an expert witness for the plaintiff in 15 legal actions involving SSRIs and has been consulted on a number of attempted suicide, suicide and suicide-homicide cases following antidepressant medication, in most of which he has offered the view that the treatment was not involved. He has also been an expert witness in one patent case, and one securities case.
Competing interests: No competing interests
Dear Editor
I found Dr Chambers’s editorial an interesting read that raises
important points including:
1. The lack of consistency across these studies (SSRIs &
teratogenicity) with respect to specific malformations and specific
drugs1.
2. These studies may be negatively affected by various factors including:
study design, number of cases, confounding factors and interpretation of
results.
3. The fact that all such studies so far did not help us towards
developing guidelines for treating depression during pregnancy that can be
useful for clinical situation.
A recently published Danish study by Pederson et al found that
prescriptions for Sertraline, Citalopram, or more than one type of SSRI
were associated with an increased prevalence of septal heart defects2.
However other studies may or may not support this finding.
In August 2009, the joint statement by the American College of
Obstetrics and Gynaecology and the American Psychiatric Association on
treatment recommendations for depression during pregnancy seems a bit
loose and does provide clinicians or patients with adequate answers. If
we were to work according to risk/benefit ratio of treat versus not to
treat. Do we really have adequate evidence to help us? Do we really
believe that clinicians know this ratio? Or how to calculate this ratio?
There is a real need for organising national and international
studies about treating depression during pregnancy to obtain more
meaningful results. This may help us to develop more adequate treatment
guidelines.
Competing interests: None
Mamdouh EL-Adl
MBBCh, MSc, MRCPsych
Consultant Psychiatrist, UK
References:
1.Chalmers C. Selective Serotonin reuptake inhibitors and congenital
malformations. The small risk of harm must be balanced against risk of
suboptimal or no treatment. Editorial, BMJ; 2009; 339:b3525
2.Pedersen LH, Henriksen TB, Vestergaard M et al. Selective
serotonin reuptake inhibitors in pregnancy and congenital malformations:
population based study. BMJ; 2009; 339: b 3569
Competing interests:
None declared
Competing interests: No competing interests
Why do pregnant women become depressed? If, as I have proposed in an
electronic discussion of depression (1) , depression is the product of an
intracerebral energy deficit, then the Daniel Atkinson energy charge
hypothesis might explain how an energy deficit might develop.
The AMP-activated protein kinase cascade is a sensor of cellular
energy charge "activated by cellular stresses that deplete ATP (and
consequently elevate AMP), either by inhibiting ATP production (e.g.,
hypoxia), or by accelerating ATP consumption (e.g., exercise in muscle).
Once activated, it switches on catabolic pathways, both acutely by
phosphorylation of metabolic enzymes and chronically by effects on gene
expression, and switches off many ATP-consuming processes" (2).
Might the demand for new protein synthesis in the mother, induced by
the hormonal changes in pregancy and/or the increasing steal of nutrient
substrate by the foetus, activate the protein kinase cascade in the
mother and thereby cause depression? Might treatment of the depression
with selective serotonin reuptake inhibitors compromise the foetus's
abilities to meet its ATP needs by inhibiting ATP production? Additionally
or alternatively in compromising the mother's ability to meet ATP needs
might selective serotonin reuptake inhibitors steal nutrients from the
foetus or even cannabalize the foetus to provide that nutrient, the heart
being especially vulnerable because of its workload?
In my electronic discussion of statin induced myopathy (3) I asked
whether statins might shift substrate dependence from glucose and fatty
acids to amino acids, my thesis being that in limiting the availablity of
fatty acids for ATP resynthesis statins might promote autophagy,
apoptosis and even necrosis of muscle cells to meet substrate needs for
ATP resynthesis. Might a similar process be implicated in the development
of congential abnormalities in the heart in babies born of mothers on
selective serotonin reuptake inhibitors?
The serotonin syndrome, seen in patients on selective serotonin
reuptake inhibitors, is charcterized by a combination of fever,
myoclonus, coma, seizures, cardiovascular collapse, and death. These
characteristics are reminiscent of those seen in malignant hyperthermia in
which muscular rigidity, tachycardia and hyperthermia develop.
Rhabdomyolysis may also develop. Acccording to Wikipedia the primary
biochemical abnormality in malignant hyperthermia is a greatly increased
Ca2+ release due to a lowered activation and heightened deactivation
threshold. The process of reabsorbing this excess Ca2+ is said to consume
large amounts of ATP and in so doing would presumably generate the
excessive heat from the increased rate of ATP hydrolysis. The muscle cell
is damaged by the depletion of ATP.
1. Kathryn Rost, Paul Nutting, Jeffrey L Smith, Carl E Elliott, and
Miriam Dickinson
Managing depression as a chronic disease: a randomised trial of ongoing
treatment in primary care
BMJ 2002; 325: 934.
2. D. Grahame Hardie *, Simon A. Hawley AMP-activated protein kinase:
the energy charge hypothesis revisited.
BioEssays. Volume 23 Issue 12, Pages 1112 - 1119
3. Sivakumar Sathasivam, Bryan Lecky. Statin induced myopathy. BMJ
2008;337:a2286
Competing interests:
None declared
Competing interests: No competing interests
Sir
I am puzzled by Professor Chambers statement on psychotherapy for
depressed pregnant women:
<<Women who prefer to avoid or discontinue drugs may benefit from
psychotherapy, although this will depend on their psychiatric
history.>>
She perhaps refers to the modern version of the old belief that
psychotherapy is pretty useless, this being that yes, CBT does help in
mild to moderate depression but is no use for major depression.
I beg to differ. I started CBT shortly after discharge from a eight week
acute psychiatric admission prompted by an acute suicidal breakdown during
my second episode of major depression. I re-started Fluoxetine, saw my GP,
saw a psychiatrist, all before my breakdown. It hit me on leaving my third
session of CBT that it would be difficult for me to become seriously
depressed ever again unless I made a conscious effort to obliterate my new
CBT skills from my mind.
Anecdotal reports from my own therapist and other experienced colleagues
concur that as far they are concerned, severe depression just takes a bit
more work to treat successfully with CBT.
The research shows that most people improve with CBT.
My point is that, given the at best 50% remission rate with anti-
depressants, we really should insist on good quality CBT _immediately_ for
depressed pregnant women. We need to abandon this grudging acceptance that
CBT may be of some use in milder cases but nothing works like drugs for
severe depression, especially since the latter assertion is demonstrably
incorrect.
Yours etc
Declan Fox
Competing interests:
None declared
Competing interests: No competing interests
Re: Spontaneous Publishing and Academic Miscarriages (SPAM)
I appreciate Professor Healy's concern that the risks of SSRI's
regarding birth
defects might be unfairly minimized. Certainly, if you are the mother of
a
child with a birth defect, regardless of the cause, it is a serious
concern and
not to be dismissed lightly. However, I did not intend for my comments to
be
interpreted as minimizing the risk; rather, I intended to place the risks
in
context both in terms of the magnitude of the risk (which is estimated to
be
relatively low compared to other known teratogens such as isotretinoin
which
can affect more than 20% of exposed pregnancies) and in terms of the
concomitant risks of non- or under-treatment.
Professor Healy mentions our California data on pregnancy outcomes
with
prenatal exposure to paroxetine. This is a perfect example of the
difficulty of
drawing conclusions from studies with inadequate sample sizes. Our data on
paroxetine were drawn from an ongoing open cohort study with an increasing
but still extremely small sample size. Preliminary results were published
in
abstract form several years ago (Unfred et al, Teratology 63:321-4, 2001)
and updated results were provided for and included in the meta-analysis
recently published by Wurst et al (Birth Defects Res Part A, Clin Molec
Teratol,
epub ahead of print, 2009). These same data were also included in a
published paper on the cumulative experience with paroxetine and cardiac
defects across several teratology information services (Einarson et al, Am
J
Psychiatry.165:749-52, 2008). As evidenced by the very wide confidence
interval and the lack of statistical significance as shown for our data on
cardiac defects in the Wurst et al paper, the contribution of this data to
a
better understanding of the relationship between paroxetine and cardiac
defects we deemed most appropriately evaluated in the context of this
comprehensive meta-analysis.
Finally, I wish to reiterate that my comments in this editorial and
elsewhere,
consistent with the joint guidelines recently released by the APA and
ACOG,
are intended to support the most appropriate treatment of the mother and
fetus in each individual situation, recognizing that there may be risks of
some treatments, as well as risks of inappropriate, under- or non-
treatment.
Competing interests:
See list of sources of grant funding
from original editorial
Competing interests: No competing interests