A Research Report to Medwatcher Japan (Yakugai Ombudsperson)

Safety of Antidepressants in Pregnancy
With Particular Reference to Paroxetine (Paxil)

July 21st 2009

Professor David Healy
Dept of Psychiatry
Cardiff University
United Kingdom
HealyD@cardiff.ac.uk
Associate Professor Derelie Mangin
Dept of Public Health & General Practice
Christchurch School of Medicine
University of Otago
New Zealanddee.mangin@otago.ac.nz

1BackgroundIn recent years there has been a marked shift among many academic
clinicians, primarily in America, toward advocating the detection of nervous
disorders in pregnant women and a treatment of these disorders withantidepressants, especially serotonin reuptake inhibiting (SSRIs)
antidepressants, where before there would have been much greater caution inusing such treatments.
It seems likely that this shift stems from the marketing efforts ofpharmaceutical companies, and perhaps GlaxoSmithKline (GSK) in particular,
who have sought to make paroxetine (Paxil) the antidepressant of choice forwomen, including women of child-bearing years.
This marketing to women of child-bearing years took shape around 1997 in
response to an initiative by Lilly for fluoxetine (Prozac) that discredited both
Paxil and Zoloft in advertising campaigns, as well as in academic symposia,
and articles in academic journals delivering a message that Prozac was muchless likely to cause physical dependence and withdrawal than Paxil.
SmithKline Beecham’s initial response was to claim that the short half-life of
Paxil meant that women contemplating pregnancy would be able to get off
treatment more readily than they would be able to get off Prozac.
This initial response was subsequently developed into a marketing position
that Paxil was the antidepressant of choice for women of childbearing years.
It was presented as a treatment for Premenstrual Dysphoric Disorder (PMDD),
as well as for the hot-flashes and depressive symptoms that accompany themenopause, and in particular for women who were pregnant or likely to
become pregnant, claiming that they could get off treatment readily if wish,,and in addition concentrations of the drug were low in breast milk andtherefore this was a suitable treatment for women during the postnatal period.
There were two key aspects to this marketing campaign; direct to consumer
advertising aimed to drive women in the reproductive years to physicians torequest Paxil for their treatment, and a sophisticated multifaceted marketing
campaign to physicians with the aim of increasing prescriptions for Paxil towomen for a range of situations – depression and anxiety, premenstrual
dysphoric disorder, social anxiety disorder as well as in pregnancy andlactation. In these ways, the marketing targeted one of the most vulnerable
groups of the population – mothers and their unborn babies.
In implementing this marketing, GlaxoSmithKline have supported educational
programmes advocating a detection of depressive disorders in women ofchild-bearing years that have downplayed the risks associated with treatment.
These risks include major birth defects and in particular cardiac defects,
spontaneous abortions (miscarriage) as well as pulmonary hypertension, preterm birth, low birth weight, neonatal withdrawal syndromes and an increased
rate of voluntary abortions. An extensive direct to consumer marketing2

campaign was mounted raising awareness and encouraging women to self
diagnose and present to their doctor with a range of psychological symptoms
labelled as anxiety, depression, social anxiety disorder and premenstrual
dysphoric disorder.
A substantial change in the culture of clinical care and prescribing for
pregnant women has been effected.
This paper will cover the issues of the nature of the evidence for treatment
with an antidepressant during pregnancy. It focuses on Paxil, but there arecomparable risks associated with other SSRIs and a number of related
medicines.
Medical professionals have a particular duty of care to women of child-bearing
years in relation to informed consent when the possibility of starting anantidepressant is raised. This duty requires women to be informed of two
risks. First there is a risk they may become physically dependent on thesedrugs, in a manner that may later make it very difficult to stop treatment once
they are pregnant or contemplating a pregnancy. Second, there is a risk thattreatment may induce major birth defects in addition to leading to a number ofother problems.
1

Do The Antidepressants Bring Benefits to Pregnancy?

This paper is written from the point of view that antidepressants work, but that
their benefits are less substantial than is commonly thought. There are no
specific trials of antidepressants in pregnancy, so evidence for benefit isextrapolated from the general adult population.
Our best data on the evidence for benefits from antidepressants come froman investigation undertaken in 2006 by the American Food and Drug
Administration, who assessing the risks of suicidality on antidepressants,
asked companies for all placebo controlled trials undertaken in depression.
They received data from trials that had enrolled over 100,000 patients (1).
In brief these trials demonstrated that 5 out of every 10 patients recruited“responded” on the outcome measure used in the trial, a physician rated
disease specific rating scale, while 4 out of 10 responded to the placebo on
the same measures.
However, there are a number of ambiguities in the word “works” as applied tothese findings. First, these results are not convincing evidence the drugs
work. They are even less convincing if it is taken into account that rating
scales other than physician rated depression specific rating scales were usedin these trials, such as quality of life scales completed by patients, but thedata using these other rating scales has remained largely unpublished andwas not analysed by FDA. Had it been analysed, it seems unlikely that any
benefit of antidepressants would have been shown on these scales.

3Second, on measures of efficacy such as the numbers of dead bodies in theactive treatment arm compared with placebo, there are a greater number ofdead bodies in the active treatment arm of antidepressant trials than there arein the placebo arm. In other words, on meaningful outcome measures thatwould command general support these treatments have not been shown to
work.
Third, the findings indicate that 4 of every 5 people appearing to respond toan antidepressant would have responded to placebo. Up to 80% of theapparent response therefore is down to placebo factors, with only 1 in 10
patients showing a specific response to the active drug.
If clinicians are to practice evidence-based medicine, on the basis of thesefindings they should resort to non-pharmacological interventions in the first
instance, and only turn to antidepressants in refractory cases. Following theevidence in this fashion would in most instances result in patients remaining
drug free in the first trimester of pregnancy.
The position we take in this paper coincides with the position adopted by FDA,
which is that this data provides at best a signal of possible efficacy, rather
than a demonstration of actual efficacy (2).
One of the hazards of the way data from controlled trials of antidepressants isread at present is that signals of possible efficacy are translated into a realuse of drug treatments as first line where in fact the evidence would not
warrant such an outcome. There has been selective publication of trials,
selective publication of data from trials, a great number of the trials as well as
opinion pieces published have been ghostwritten. It is likely that thisghostwriting has contributed to a misleading impression of efficacy.
A matter of significant concern in recent years has been the mass screeningof pregnant women with rating scales for anxiety and depression, high scoreson which are likely to translate into prescriptions of SSRIs.
There is no reason to believe that the results of a controlled trial ofantidepressants in pregnancy would yield results significantly at odds with thefindings above.
A reasonable clinical approach to prescribing in general should balance theevidence of benefits against that of hazards for a new drug over existing
effective medicines or no treatment. The slender evidence for efficacy outlined
here needs to be balanced when prescribing in pregnancy against bothforeseen and unforeseen fetal harms. The foreseen harms inform allprescribing but given the presence of a third party, the foetus, the possibility of
unforeseen harms has underpinned the traditional principle that medications
should be avoided in pregnancy if at all possible and in particular in the firsttrimester where the potential for malformations is the greatest, and because
those malformations or other injuries can have devastating and lifelong
consequences for both parents and child.

42
The Risks of Leaving Antenatal Depression Unmedicated
It is common to find statements now in the academic literature to the effectthat 35% of pregnant women have depressive symptoms and that 10% ofthem are depressed (3,4). It is also common to find articles and editorials
claiming that the consequences of not treating pregnant women with nervous
problems with antidepressants far outweigh any adverse effects of treatment(5, 6).
However, one problem with this formulation is that having symptoms, evenmeeting every single one of the operational criteria for depression, does notnecessarily mean a person is depressed. Making a diagnosis in these cases
simply on the basis of a symptom tally is a profound clinical mistake.
Many of depressive symptoms arise in states of stress – such as pregnancy.
Treating for depression on the basis of a depressive symptom count would
return us to the days when medical adverts openly advocated treating
hypertensive or asthmatic patients with benzodiazepines as these were
supposedly clearly stress related disorders.
When arguments for treating antenatal depression are put forward, they statethat untreated depression leads to smoking, alcohol and drug intake, poor
self-care, suicide and postnatal depression (5,7). They furthermore infer that
there may be a direct toxic effect of untreated depression on the foetus.
Finally they point to effects of untreated antenatal depression on thedevelopment of the child in later life, arguing that these are substantial anddeleterious.
The prevalence of major depression is often overstated in these arguments
for treatment. The point prevalence of major depression is (or ‘around 4%’)4%, 5% and 3% in the first second and third trimesters of pregnancy (8). This
group can be further examined to determine the true hazards of depression inpregnancy.
As a first step here we must distinguish melancholia or what has also beencalled endogenous depression or a severe depressive disorder with or without
psychotic features, from conditions commonly labelled as depressions,anxiety disorders, or mixed anxiety-depressive disorders, or neurotic orreactive depression.
There are no known direct toxic effects of these latter non-melancholicantenatal “depressions” on the foetus. The foetus is isolated from the motherand is comparatively immune to maternal influences, other than infections or
drugs that cross the placenta. There is for instance no known endocrinechange linked to these common nervous disorders that affect pregnant
women that could affect the foetus.
The only psychiatric disorder for which there is any proven endocrine
abnormality is melancholia, and even in this case the endocrine disturbances
are of a lesser degree to those found in severe physical stress or frank5

endocrine disorders, and neither of these states are associated with birthdefects.
Melancholia in pregnancy is furthermore rare. The traditional wisdom is that
this disorder can arise in pregnancy, but that it very commonly clears withbirth, and does not extend into the postnatal period (8). This suggests thatsuch disorders may have a hormonal basis.
In contrast to melancholia, the situation for women when it comes to the lesssevere nervous disorders more likely to stem from social factors that might belinked to pregnancy would appear to be better now than formerly. Within
living memory, pregnancy was the condition most likely to lead to a woman’s
death, it commonly resulted in immediate post-partum health complications
such as infections or haemorrhages and enduring complications such as
uterine prolapse, incontinence and other difficulties, babies were often
stillborn or died shortly after birth, and the process of labour was uncontrolled
so that it might endure for up to a week with little or no analgesia. There was arecognised terror of parturition.
As regards the risk of suicide noted above, suicide is a highly culture specificdisorder. The management of this risk should therefore vary from culture toculture. The data on the frequency of suicide in pregnancy is of extremely
poor quality, but there are indicators that suicides have fallen in recent
decades in the West, with suggestions that in part at least suicide was a
response to a problematic pregnancy (8). If suicide in pregnancy is commonlya response to a problem posed by a pregnancy, an antidepressant would
seem unlikely to offer a good answer, especially as in placebo controlled trialsof antidepressants there are more suicides in the active treatment arms ofthese trials than in the placebo arms (3).
As regards the risks of substance abuse stemming from untreated depression,
if there were evidence that depressed women take up drinking or smoking
early in pregnancy, where they had been abstinent before, there might be acase for ensuring that depression was treated even if that involved medication.
But there is no such evidence. There is also no evidence that the treatment of
substance abuse that has an onset in pregnancy shows a response toantidepressants. In either the case of women with established smoking andalcohol abuse or onset during a pregnancy, we have no data on the risks ofcombining the hazards of smoking, alcohol, or other substance abuse andantidepressant intake, if antidepressant intake does not lead to an immediate
cessation of these other substances.
The foetus does not distinguish between prescription and non prescription
medicine in terms of effects and nor, for that matter, does the mother. In thecase of substance abuse in general, the key issue is whether the risks ofteratogenesis are greater with agents like paroxetine or fluoxetine than withcocaine or smoking for instance. Laboratory studies outlined below now
indicate that the risks of birth defects on an SSRI like Paxil are greater thanwith a serotonin reuptake inhibitor such as cocaine (9).

6

Postnatal depression does have effects on the bonding between mother andchild and does affect the physical and mental development of the child,leaving them prone to affective instability in later life and with impaired
cognitive performance relative to their peers in childhood (8). There ishowever no evidence that antenatal depression does this.
In addition, the link between antenatal and postnatal depression isoveremphasized. While first trimester depression is a risk factor for post natal
depression, most (71%) first trimester depression does not go on to post natal
depression and most (64%) post natal depression is not associated with firsttrimester depression (10). If antenatal depression leads to a postnatal
depression, there is always the opportunity to treat the depressive disordervigorously in the postnatal period.
In the event that it is thought that a particular antenatal depression or anxiety
state needs active treatment rather than simply judicious monitoring andhygienic measures, there are treatments other than antidepressant drugs.
For mild to moderate depressions, there are interpersonal therapy (IPT) andcognitive behavioural therapy (CBT), which for conditions of this level ofseverity are as efficacious as drug treatment and can moreover now bedelivered by computer in a cost-effective fashion. Indeed, given the role ofsocial factors associated with the nervous states found in pregnancy, it isworth noting that IPT originated in part as a treatment for postnatal depressionthat focuses on social and interpersonal issues and that it would appear
accordingly to be particularly suitable for antenatal disorders.
For the rare severe or melancholic depressive disorders, treatment options
include the use of non-serotonin reuptake inhibiting tricyclic antidepressantsor even serotonin reuptake inhibiting tricyclics as the hazards of treatment
seem likely to stem from potency of uptake inhibition and the tricyclics are in
general less potent serotonin reuptake inhibitors, and these antidepressantsrather than SSRIs are recommended by guidelines such as those issued by
Britain’s National Institute for Health and Clinical Excellence (NICE). Whereavailable, electroconvulsive therapy (ECT) offers a further option.
3
SSRIs & Teratogenesis
Many academic texts, and review articles, and other pronouncements convey
an impression that the evidence regarding the risk of teratogenesis isequivocal (1, 2). This is extraordinary given the data, and needs explaining it
its own right.
In 2005, GlaxoSmithKline were required by FDA to change the warning label
on paroxetine to a pregnancy category D. This change was consequent on a
study undertaken by the company in 2005 but only published in 2007 - 2
years later (11).
As of 2008, this study by GSK and 14 other studies had been reported from1998 onwards (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26) that7

contained paroxetine specific data and were adjudged by GlaxoSmithKline tobe sufficiently methodologically sound to include in a meta-analysis (27).
These included case cohort and medical records studies. Overall the studies
GSK analysed gave a clear risk of major defects for paroxetine taken in thefirst trimester with an odds ratio of 1.3 (C.I., 1.1, 1.6) and an odds ratio for
specifically cardiac defects of 1.5 (1.2, 1.9). In terms of figures on the risks ofoverall defects 10 studies gave an increase in the odds ratio of a defect, 3gave a decrease and 2 returned a relative risk of 1.0. In terms of cardiac
defects, 9 studies gave an increase in the odds ratio of a defect, 3 indicatedno increase in risk while 1 study returned a figure of 1.0.
(A plot of these studies has been compiled by GlaxoSmithKline and presented
on their website. We produce the plot for all major birth defects and forspecifically cardiac defects in Appendix 1).
Of the studies that did not support a risk of paroxetine, some indicated a clear
risk on other SSRIs (26), while many of the studies pointing to risks withparoxetine also point to risks with other SSRIs.
Two further studies were considered by GSK to be methodologically soundbut were not included in the analysis. In one, there was a marked increase ofrisk for both cardiac defects and major birth defects on antidepressantscompared to non-treatment but also an interaction between antidepressantsand benzodiazepines (28). In the second, there was no data for specificantidepressants but again an increase in risk with antidepressants compared
to non-treatment (29).
Cause and EffectSome have claimed that the only way that a birth defect could be causally
related to antidepressant intake is by means of controlled trials. But in fact
there is no basis for the claim that RCTs are necessary for a demonstration ofbirth defects, and in fact no birth defect has ever been established on thebasis of a controlled trial. Indeed, few if any significant adverse effects of adrug, birth defect or otherwise, have been demonstrated by means ofrandomized trials.
Randomized trials are a subset of epidemiological studies that control for
confounding influences by a particular method. This method often allows amuch smaller sample of subjects to be recruited, although in this case thesample size is unlikely to be smaller than in a cohort study. While RCTs
ordinarily benefit by being able to recruit fewer subjects, they commonly giverise to concerns that the samples recruited to such studies are homogeneousto the point that the findings from such studies may not generalise to typicalclinical settings.
Those who argue that current data about the hazards of antidepressants,
arising from the studies that have already been undertaken, have not beenconclusive offer an argument in defence of their position that hinges around a8particular and incorrect interpretation of point estimates and their related
confidence intervals.
Typically the argument is if the 95% confidence interval around the odds ratio
for a hazard includes the figure 1.0, there is no risk. This interpretation iswrong.
If the point estimate for the odds ratio is itself 1.0 or shifted to the left of 1.0,
there is unlikely to be a risk – but still could be a risk. But if the point estimate
lies to the right of 1.0, there is likely to be a risk, and if a large majority ofstudies using different methods find an equivalent shift to the right, as
GlaxoSmithKline have found, then it is highly likely there is an increase in risk.
If the data are shifted to the right, but the 95% confidence interval still includes
the figure 1.0, this does not mean there is no increase in risk – it is more likely
to mean the study is underpowered or there are factors others than a simple
undifferentiated risk in all those exposed to treatment.
This can be brought out by a thought experiment. Assume a doctor is forced
to put a patient, likely to become pregnant, on one of two drugs for a particularclinical condition, both of which come with a risk of birth defects. If drug A has
an odds ratio of 1.8 with a 95% confidence interval stretching from 1.1 to 2.5,
and drug B comes with an odds ratio of 5.4 with a 95% confidence interval
stretching from 0.92 to 25.2, the drug to recommend the patient should take isdrug A rather than drug B. The data suggests drug B is likely to be threetimes riskier than drug A.
Against this background, consider the question of when the epidemiological
data began to point conclusively to the existence of a risk of birth defects. Asof 2002, there were 4 studies available. The Kulin study from 1998 (12),which pointed to an odds ratio of a birth defect on paroxetine compared to
non-treatment of 1.8 (95% C.I., 0.6, 5.4).
Second, a further study that appeared in 2001 from Unfred and colleagues(13) showing a rate of major malformations of 4.2% Paxil vs. 0.05% forcontrols. This is a greater than 8-fold increase in risk on Paxil. This study
has remained unpublished as of 2009.
Third, another study that appeared in abstract form in 2002 from Diav-Citrin(30) and colleagues in 2002 that had a rate of 3.9% for major malformations
on paroxetine vs. 2.1% in controls. This study was only published in 2005.
Fourth a study by Simon et al (14) which showed an odds ratio of major
malformations for paroxetine of 0.7 (95% C.I. 0.0, 13.5).
Combined these studies and the consistency between them as of 2002 madea strong case that there was a real increase in risk. In part this evidence ofrisk may not have come to wider attention because 2 of the 4 studies as of2002 were unpublished and 1 remains unpublished.

9The Kulin et al (12) paper also reports an excess of therapeutic andspontaneous abortions on treatment. Combining the data offered for
spontaneous and therapeutic abortions gives 20.2% on SSRI versus 12.7%
for controls; an odds ratio of 1.7 (95% CI 1.1, 2.9). In the case of
spontaneous abortions alone, the figures are 13.5% compared to 8.9% forcontrols; an odds ratio of 1.6 (95% C.I., 0.9, 2.9).
When data on spontaneous abortions are reported in the cohort studies cited
above, they consistently point to an excess in women taking antidepressants.
If spontaneous abortions are linked to a greater frequency of birth defects
than term births, as is commonly suggested, then the true rate of birth defects
linked to antidepressant intake seems likely to be substantially greater thanestimates based on term births only.
Causality in the Laboratory
When assessing causality, it is traditional to marry epidemiological withmechanistic or laboratory studies. When the issue involves a birth defect,
such studies are usually undertaken in animal populations.
It has been known for 40 years that serotonin has a trophic function inembryogenesis, regulating cell migration in tissues such as the embryonic gut,heart and nervous system ( 31, 32, 33, 34, 35). Despite this, as of 2009 there
had been no rigorous published studies looking at the possible teratogenic
effects of SSRIs.
In 2009, a study covering this issue was published (9). It is worth considering
the origins of this study. The researchers were working for Schering-Plough
who had bought Organon and in the process acquired several SSRIs. As partof work to establish whether these could be brought to the market they
undertook a detailed study to compare the teratogenic potential of these drugs
with a series of SSRI antidepressants on the market, along with otherserotonin reuptake inhibitors such as cocaine and drugs with a known
teratogenic potential.
This study demonstrated clear teratogenic effects for a number ofantidepressants, in particular serotonin reuptake inhibitors, and especially withparoxetine (9). The findings for paroxetine were dose-related and consistent
with what is known of the trophic effects of serotonin in the development of
the embryo. The signal was stronger for paroxetine than for other serotonin
reuptake inhibitors such as cocaine, and equivalent to known teratogens suchas retinol.
The findings from this laboratory study are consistent with the pattern ofdefects that have emerged in epidemiological studies in recent years. The
study led Schering-Plough to abandon the development of their SSRIs, eventhough the problems seen with these molecules were of a lesser severity thanthe problems seen with Paxil.
At present the data is best explained in terms of potency of action on theserotonin reuptake site. This suggests the problems may be dose dependent,

10

for which there is some evidence (22). If an action through serotonin systems
is the mechanism through which these drugs pose a risk, then all tricyclic
antidepressants that inhibit serotonin reuptake pose some risk, perhaps
dependent on dose, as do many antihistamines.
It appears from this study that paroxetine and many other antidepressants arelikely to pose a greater risk than for instance drinking alcohol in moderation.
The traditional method of handling the risks posed by alcohol has been toencourage women to abstain completely from alcohol while pregnant – which
seems diametrically the opposite position to that advocated by those
supporting a use of antidepressants in pregnancy.
4
Other Hazards
Aside from teratogenic effects outlined above, there is now a consistent bodyof evidence linking antidepressants with prematurity, as well as low birthweight (36, 37), and pulmonary hypertension (38) when given in the course of
pregnancy.
These problems appear independent of any depression or nervous disorder.
A study with a large sample size (n = 1451) found that children of mothers
who take SSRI antidepressants for depression appear to have worse
outcomes than those of mothers with depression who do not takeantidepressants in terms of birth weight and respiratory distress even whenmaternal illness severity was accounted for (28).
Finally, there is little dispute that antidepressants can trigger a neonatal
withdrawal syndrome after birth. This was first noted in 1972 (39). The risk
seems most clearcut in the case of paroxetine, for which there has been agreater number of reports to regulators of dependence and withdrawal effects
than for any other psychotropic drug, both in those taking the treatment and inneonates (40, 41, 42, 43, 44, 45, 46, 47, 48, 49). While in some cases, thissyndrome is mild, it can also be serious leading to convulsions andnecrotizing enterocolitis.
At present, in addition to an excess of spontaneous abortions on SSRIs there
also appears to be an excess of voluntary abortions. This seems unlikely tostem from women believing their child might have been injured by treatment
as almost all expert sources claim that no such injuries happen.
It is surprising that there appear to be no efforts to determine what mightunderpin this excess. In some cases gross abnormalities may have been
revealed on scan. A further possibility lies in the profile of effects of SSRIs.
These are anxiolytic agents and this anxiolysis leads in some instances toprofound disinhibition, accompanied by impulsive behaviour, where thesubject is heedless of the consequences of their actions in a manner quite atodds with their normal personality (50). This is particularly likely to be thecase when combined with alcohol.

11

A further issue to consider is the growing body of evidence that abortions,
whether spontaneous miscarriages or voluntary terminations, may increase
the risk of subsequent mental health problems, including substance abuse( 51, 52). If Paxil has as large an effect on spontaneous miscarriage andabortion rates as it appears to have, these miscarriages and abortions may belaying the basis for a considerable amount of future problems with substancemisuse.
5
Antidepressants & Withdrawal
Any question of the possible teratogenic effects of antidepressants needs totake into account the physical dependence that all antidepressants can cause,
but SSRIs cause in particular and within the SSRI group paroxetine andvenlafaxine do to an even greater extent than others. Some background on
the history of dependence on Paxil is attached in an Appendix2.
The specific problem that dependence on Paxil and related drugs causes asregards birth defects is that women of child-bearing years put on these drugs
are commonly not informed that they may become dependent on treatment
and may be unable to get off treatment or that the treatment may induce
major birth defects, as well as pulmonary hypertension, preterm birth, lowbirth weight and a neonatal withdrawal syndrome. Up to one third of women
become pregnant by accident. While on treatment therefore many women
may end up several months pregnant before they are aware of being pregnant.
Even if aware of being pregnant from the day of conception they may not beable to get off treatment in time to avoid a risk of major birth defects.
There is furthermore no understanding of what gives rise to antidepressantdependence syndromes. The advice usually given involves slow tapering.
This works for some but in the case of birth defects as noted above it willcommonly work too slowly to avoid the risk of birth defects.
In the absence of agreed procedures to manage difficult withdrawal
syndromes, an indeterminate number of women of child-bearing age put on
antidepressants will find it difficult or impossible to stop treatment should theywish to have a drug-free pregnancy.
6
Changing Therapeutic Cultures
The evidence outlined here shows the balance of risks and benefits for Paxil
use in pregnancy provides no support for its use in this clinical situation andlittle support for the use of other antidepressants. But current clinical practiceand opinion is increasingly at odds with the evidence. How did this situation
come about?
Until very recently, the standard clinical view was that all medicines, including
antidepressants, should be avoided in pregnancy, unless there was a clear
clinical need. While older textbooks still offer this view, there are few recent
studies or reviews in mental health and related journals that point to theexistence of hazards of treatment or argue against treating antenatal nervous

12

conditions with antidepressants. Given the clear evidence of risks stemmingback almost a decade, and given that following the currently available
evidence as regards the benefits of treatment would suggest not medicating
too quickly, this switch in treatment philosophy calls for an explanation in its
own right.
There is convincing evidence that a number of the reviews in this domain
advocating treatment or denying hazards of SSRI have been published understrong influence of pharmaceutical companies. Some papers have been
ghostwritten (53) or commissioned by companies (54) , or have been written
without the competing interests of their authors being revealed (55). It is also
clear that many of the leading figures in women’s mental health, at least in the
United States, have been heavily sponsored by pharmaceutical companies(56). This undermines the ability of physicians to assess in a reasonable way
the available information about these products in order to make the best
decisions for their patients
Quite recently there was controversy surrounding the use of antidepressantsfor children. At the time the controversy blew up, the vast amounts ofliterature appears to have been written by either company personnel ormedical writers, even though in a number of instances it was published under
the names of distinguished academics. There was an almost complete
mismatch between what the data from studies actually demonstrated when it
was possible to get access to this data and what it was claimed in academic
literature and meetings these studies had shown.
There appears to be a close to comparable situation in the domains ofdependence on and birth defects linked to the use of SSRIs with companies
like GlaxoSmithKline having interacted with academics to engineer an
extraordinary change in the culture of clinical care. It is all but impossible toknow the full extent to which the sources of information relied upon byphysicians has become adulterated by the influence of companies.
To avoid harm to women of child-bearing years and their children by
restricting the use of antidepressants to these women, we suggest that prior
to starting treatment it should be mandatory to inform all women of the risks
that treatment may induce major birth defects, miscarriages and otherhazards and also of the risk of dependence on these drugs that might lead toan inadvertent or unavoidable involuntary exposure of the unborn child to therisks stemming from its mother’s medication.

13

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