"In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis"

The title heading this post - "In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis" - comes from the findings published by Annemette Halvorsen and colleagues [1] on a topic that has been of some research interest for quite a few years (see here and see here for example).

SSRIs denote a class of medicines called the selective serotonin reuptake inhibitors, principally used to treat/manage various types of depression. Although in quite a few cases a lifesaver, such medicines also come with a risk-benefit profile (same as all medicines), a risk-benefit profile that also extends to their use during important times such as pregnancy. Minus any scaremongering sentiments, for quite a while now, there has been some interest in whether SSRI use during pregnancy *might* have some important implications for offspring health and development [2]. Such *associations* whilst potentially important, need of course to be balanced with the reasons why SSRIs are used, and how for example, depression is not typically something that magically disappears as and when a woman becomes pregnant...

The Halvorsen paper represents a "systematic review and meta-analysis" of the pertinent research literature examining whether "in utero exposure to selective serotonin reuptake inhibitors (SSRIs) is associated with increased risk of developing mental- or behavioral disorders." Such a 'boiling down'  of the research literature was, we are told, "conducted in adherence with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline" and specifically covered in connection to various childhood developmental labels such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

Based on their analysis of the available data - "20 studies were included in the review and results from 18 of these were meta-analyzed" - researchers observed "a statistically significant positive association between in utero exposure to SSRIs and mental- or behavioral disorders such as autism spectrum disorder..., attention-deficit/hyperactivity disorder... and mental retardation." I say that with the suggestion that intellectual (learning) disability might be a more appropriate description for that last label mentioned. The authors caution however that their results do not necessarily mean that prenatal SSRI exposure *causes* something like autism or ADHD: "these associations do not necessarily reflect a causal relationship since the results included in this meta-analysis are likely affected by residual confounding by indication, which is likely to account for some (or all) of the positive association."

So what to make of this research? Well 'it's complicated' is the long-and-short of it. Minus any sweeping generalisations I'll take you back to some other research (see here) that did try and disentangle the 'causality' side of this area of study (whether underlying maternal depression or antidepressant use was the most important variable). The findings reported by Rai et al [3] did [cautiously] talk about how "children exposed to antidepressants during pregnancy seemed to be at a higher risk of autism, particularly autism without intellectual disability, than children of mothers with psychiatric disorders who were not treated with antidepressants during pregnancy." Other research however has observed something rather different (see here). Y'see, it's complicated.

So all I can really say is that more research is required, and if in doubt, talk to your prescribing physician.

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[1] Halvorsen A. et al. In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis. Acta Psychiatr Scand. 2019 Apr 2.

[2] Pedersen LH. et al. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ. 2009;339:b3569.

[3] Rai D. et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017;358:j2811.

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Pregnancy depression (with or without antidepressant use) and offspring autism risk continued

"Women with depression during pregnancy have an increased risk of having a child with ASD [autism spectrum disorder], regardless of antidepressant use."

That was the conclusion reached by Katrina Wilcox Hagberg and colleagues [1] following their analysis of the UK Clinical Practice Research Datalink (CPRD). Their study was carried out as a result of the still-rumbling-on question of whether pregnancy depression or the pharmacological treatment of depression during pregnancy *might* be a risk factor for an offspring diagnosis of autism (see here and see here). As you might appreciate, it's difficult to pin down whether depression or the treatment of depression is the more important issue given that the two typically appear together.

The CPRD held here in Blighty is a mighty fine resource and has been used to examine all-manner of potentially important issues (see here and see here for some examples). Researchers looked at mums and offspring ("singleton infants") born between 1989 and 2011 totalling nearly 200,000 mother-baby pairs. They reported that: "Mothers were required to have at least 12 months of recorded history before the baby's delivery date, and the children were required to have at least 3 years follow-up after birth." Because antidepressants require a doctor's prescription in the UK, they were also able to identify those other important elements vital to this study: depression and it's antidepressant intervention or not, as well as "the timing of antidepressant use during the exposure period." Authors also report some additional analyses based on "a sibling case-control analysis of maternal pregnancy exposures in ASD cases compared to non-ASD siblings of the same mother."

Results: based on the examination of 'read codes', authors identified some 2100 children with a diagnosis of ASD. The old 4:1 male:female ratio yet again held true (see here). Taking into account being exposed to depression or not and whether exposure was treated or untreated, researchers formed their headline conclusion on pregnancy exposure to maternal depression being linked to an increased risk of offspring autism. Further: "The risk was slightly higher among women with treated depression... compared to untreated depression." The results of the sibling case-control part of their trial - "601 same-sex siblings who did not have an ASD diagnosis matched to 531 ASD cases" - also revealed that: "the risk of ASD in offspring of mothers with untreated depression was 1.18 (95% CI 0.64-2.20) and 1.53 (95% CI 0.89-2.62) for treated depression, compared to unexposed." Some further analysis looking at the timing of antidepressant exposure during pregnancy revealed that it didn't really matter when the exposure happened (i.e. which trimester).

Perhaps contrary to some of their findings, it's clear from some of the statements included in the Hagberg paper that the authors seem to have sided with the idea that "antidepressants are not themselves associated with the increased risk" of offspring autism. It's depression that is the important factor, and the "slight increase in risk with antidepressant use reflects differences in the underlying severity of depression." The other evidence they draw on to support their assertion is the "finding that the risk of ASD was not elevated in women who were prescribed antidepressants for other indications."

I'm not however so sure that we can be so certain about such a siding. I say that on the basis that researchers "did not evaluate the effect of antidepressant dose in this study" and: "Drug information in the CPRD covers written, but not dispensed prescriptions" so therefore they "cannot be sure that women used all the prescribed antidepressants." Their 'nested sibling case-control analysis' also revealed that: "the risk of ASD in offspring of mothers with untreated depression was 1.18 (95% CI 0.64-2.20) and 1.53 (95% CI 0.89-2.62) for treated depression, compared to unexposed." Not proof positive by any means, but interesting. I'm also inclined to direct you to other studies previously discussed on this blog, where the finger of suspicion has not rested entirely with maternal depression [2]. Indeed, where meta-analysed data [3] has been more partial to the idea that prenatal exposure to certain antidepressant formulations could still be on the menu with some offspring autism risk in mind.

Obviously one has to be very careful when talking about this area of autism research. Much like when another class of important medicines used during pregnancy are talked about with 'autism risk in mind' (see here), such medicines are not typically prescribed or dispensed willy-nilly without good reason. By saying that, I feel I must repeat my oft-said caveat on this blog: no medical or clinical advice is given or intended; if in doubt, talk to your prescribing physician.

But the weight of evidence produced so far has not let antidepressant use off the research hook just yet. And drawing on data suggesting that the frequency of depression during pregnancy might be on the increase (see here), one should perhaps also suspect that this could have something - a small part at least - to do with the ever-increasing rates of autism...

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[1] Hagberg KW. et al. Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring. Clinical Epidemiology. 2018; 10: 1599-1612.

[2] Raj D. et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017; 358: j2811.

[3] Andalib S. et al. Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review. Eur Psychiatry. 2017 Sep;45:161-166.

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On Cochrane and 'facts' and 'politics' in evidence-based medicine

The controversy surrounding the reported expulsion of Peter Gøtzsche from the Cochrane Collaboration (or should that just be Cochrane?) is something that I've been following for a few days now (see here). Cochrane, under the heading "Trusted evidence. Informed decisions. Better health", represents one of the premier go-to sources for evidence-based healthcare advice on a range of topics. Some of those topics have been previous fodder for this blog too (see here and see here for examples).

I don't profess to have any unique insight into the various goings-on leading to the reported expulsion of Gøtzsche and resignations of fellow members beyond that which has been discussed in various sections of the science media (see here and see here and see here). From what I gather, things look like they've been 'brewing' for a while with regards to Cochrane and the views and opinions expressed by some of those who are seemingly departing. Such a public spat however, is unlikely to be good for science or evidence-based medicine, and indeed may have some wider implications for some fundamentals of science and science communication...

One of the possible [late] precipitating events mentioned around the Gøtzsche saga was the publication of a quite scathing article by Lars Jørgensen and colleagues [1] (including Gøtzsche as an author) questioning the published results of a recent Cochrane review [2] titled: "Prophylactic vaccination against human papillomaviruses [HPV] to prevent cervical cancer and its precursors". The original review by Marc Arbyn et al garnered media headlines when published (see here) as per conclusions such as: "There is high‐certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26." A comforting finding by all accounts. Accompanying such efficacy data were other statements made by the authors on the basis of the evidence reviewed that: "The vaccines do not increase the risk of serious adverse events, miscarriage or pregnancy termination."

Jørgensen and colleagues however put forward their [peer-reviewed] view that the Arbyn paper fell short of the expected standards from Cochrane: "We do not find the Cochrane HPV vaccine review to be ‘Trusted evidence’, as it was influenced by reporting bias [3] and biased trial designs." They highlighted several 'issues' with the original review stretching from trial selection for the review, to the assessment of "serious and systemic adverse events" to potential "conflicts of interest." Similar sentiments had been voiced about other Cochrane reviews too that were subsequently pulled from the scientific literature. Feathers were inevitably ruffled (see here) by the Jørgensen paper, even as far as prompting a response from the journal that published the paper [4] about the peer-review process leading to publication of the critique. Things are getting serious when a journal has to defend its publication of a paper.

Without wishing to reduce this saga to any one event, I don't think it would be unreasonable to assume that the Jørgensen paper might have influenced matters quite considerably; perhaps even bringing them to a head. As per involvement on the Boesen paper [5] Gøtzsche is no stranger to calling out Cochrane reviews that seemingly don't make the grade, alongside also voicing opinions on various other matters down the years. To quote: "... in another book, [he] likened the pharmaceutical industry to "organized crime""; such forthright statements stretching back some years are unlikely to have made too many friends in certain circles.

As per the title of this post mentioning the words 'facts' and 'politics', one particular write-up of this saga I think hits the nail on the head. The opinion piece from Trish Greenhalgh [6] presents the two sides to this 'dispute': on the one hand is that the “crisis” is "philosophical (relating to the nature of facts)" and on the other, "political (relating to organisational governance)." The philosophical side of things is pretty evident as per the publication of the Jørgensen paper as a counter to the Arbyn paper. Greenhalgh mentions about how "Gøtzsche might be classified as an evidence-based medicine purist" given his views and sizeable contribution to various "statements on how to undertake and publish research." In this respect, his published views on the original Arbyn paper (and similarly in other reviews) seem to detail scientific standards not being met, or at least not being met to his and his co-authors standards. And certainly on points such as access to trial results and data, he's seemingly not alone in his concern (see here).

On the political side of things, well, at the time of writing we just don't know enough to reasonably comment. Greenhalgh mentions that: "The political explanation for Cochrane’s crisis relates to the tension between governing an organisation and respecting individual members’ academic freedom to express dissent." The fact that such dissent has over the years covered various important public health topics - "cast doubts about the safety of a vaccine against human papillomavirus (HPV), a cause of cervical cancer, and says psychiatry has “gone astray” by coercing patients into taking medication, such as antidepressants, they don’t want to use and that cause “brain damage” over the long run" - is likely to have really stretched those organisational relationships with Gøtzsche. Not least because immunisation and antidepressant use reflect important pillars of modern public healthcare and, historically, uptake of such medicines is very, very susceptible to differences in scientific views, opinions and beyond.

As to the idea mentioned by Greenhalgh that: "We should cut it [Cochrane] some slack while it gets its house in order", I'm not exactly sure how it's going to approach this 'house in order' requirement and what this means for the future credibility of Cochrane. Based solely on the 'facts' side of this saga, it strikes me that organisations like Cochrane actually need people like Peter Gøtzsche and their "evidence-based medicine purist" beliefs. They need them in order to critically (really critically) boil down the ever-growing research literature into scientifically sound statements for public and policy consumption without fear or favour. Minus such voices, it's more likely that evidence-based messages originating from such initiatives are perhaps going to be weakened, which in turn means that population healthcare is potentially going to suffer. Moreover, I assume also that just because Gøtzsche is reportedly not part of Cochrane any more does not mean that he won't be heard from again in the peer-reviewed domain...

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[1] Jørgensen L. et al. The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. 2018. July 27.

[2] Arbyn M. et al. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev. 2018 May 9;5:CD009069.

[3] Jørgensen L. et al. Index of the human papillomavirus (HPV) vaccine industry clinical study programmes and non-industry funded studies: a necessary basis to address reporting bias in a systematic review. Syst Rev. 2018 Jan 18;7(1):8.

[4] Heneghan C. & Onakpoya I. Editors’ response to concerns over the publication of the Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. 2018. Sept 12.

[5] Boesen K. et al. The Cochrane Collaboration withdraws a review on methylphenidate for adults with attention deficit hyperactivity disorder. Evid Based Med. 2017 Aug;22(4):143-147.

[6] Greenhalgh T. The Cochrane Collaboration—what crisis? BMJ. 2018. Sept 17.

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Carefully: effect of SSRI use on "rating-scale-assessed suicidality in adults with depression"

I stress the word 'carefully' in the title of this post discussing the findings reported by Jakob Näslund and colleagues [1] because it covers the very sensitive idea that "selective serotonin reuptake inhibitors (SSRIs) have been claimed to elicit or aggravate suicidal ideation."

I think it's sensible to begin this post by stressing that (a) NO medical or clinical advice is given or intended on this blog, and (b) anyone with concerns about their taking this class of medicines really needs to speak to their physician BEFORE making any changes to their prescribed medication routine. I know that point (b) sounds like me giving medical / clinical advice but it's common sense to talk to your medical professional first who's spent years studying and probably years practising medicine, rather than tinker around yourself...

There is always a balancing act to consider when discussing research such as this. A medicine indicated for various clinical conditions, that is taken by many, many people, and quite successfully treating / treated (nay, very successfully [2]) a condition that can, without treatment, have life-limiting consequences. No-one wants to rock the boat and scare or deter people from accessing such a treatment. At the same time however, one needs to know everything about that medicine; not least whether for some, there may be side-effects to possibly consider...

It's been a quite a long running saga talking about the possible additional effects of SSRI use for some (see here). It's drawn heavily on often harrowing individual stories and perspectives and not also been helped by the seeming (in)actions of some of the manufacturers of such medicines (see here). Näslund et al decided to approach this delicate topic from the point of view of analysing "the effect of [SSRI] treatment on rating-scale-assessed suicidal ideation in individual patients." This is distinct from other work that has focused on actual suicides or "suicide-related adverse events" that have been carried out before. The authors suggested that their approach might have the advantages of measuring the "net influence of treatment on suicidality at a group level" as well as the ability to "detect individual cases of emergence or aggravation of suicidal ideation." To this end, scores on the Hamilton Rating Scale for Depression (HRSD) particularly focused on "item 3 of the HRSD" covering suicidal ideation/attempts, was a core feature of their study covering "young adults (18–24) (n = 537) and adults (≥25) (n = 7725)." Said participants were derived from "all industry-sponsored, HRSD-based, FDA-registered placebo-controlled studies undertaken to explore the effects of citalopram, paroxetine or sertraline in major depression in adults."

Results: "In patients above the age of 24, SSRIs were found to reduce the mean rating of the HRSD suicidality item from week 1 until study end-point and also to reduce the risk for aggravation of suicidal ideation and emergent suicidal behaviour." This is very good news. It provides "strong support for the view that the net effect of SSRI treatment is beneficial rather than harmful" when it comes to suicide ideation/contemplation bearing in mind the specific focus on on item on the HRSD. I will again link to the recent findings by Cipriani and colleagues [2] reporting that: "All antidepressants were more efficacious than placebo in adults with major depressive disorder." It doesn't, as Näslund et al suggest, rule out rare cases of 'adverse effects', but does suggest that any such extreme side-effects are not likely to be encountered by most people who take such medicines.

When however it came to those younger adults (aged 18-24 years), the results were a little less straight-forward. So: "In young adults, those given an SSRI were at enhanced risk for worsening of suicidal ideation (in the unadjusted analysis) or emergent suicidality (loose but not strict definition) during the late (weeks 3–6) but not the early phase (weeks 1–2) of treatment." You'll see from the number of brackets used in that last quote that the authors provide some caveats to such findings; but this shouldn't take away from the trends observed. Indeed, bearing in mind such findings and also that "both SSRIs and placebo resulted in an end-point rating of suicidality equal to that observed in adults given an SSRI and lower than that observed in adults given placebo" you kinda get the impression that further investigations are needed to ascertain for example, whether depression and/or suicidality in the 25 and overs is somehow 'different' from depression in the younger age group. At least, different insofar as what treatment choices might be primarily made available. No, I'm not saying that this is evidence enough that SSRIs should have some sort of age restriction, just that cost/benefit ratios might perhaps have to be a little more 'age-sensitive' as well as individual-sensitive.

And, if anyone needs someone to talk to, there are resources available.

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[1] Näslund J. et al. Effects of selective serotonin reuptake inhibitors on rating-scale-assessed suicidality in adults with depression. Br J Psychiatry. 2018 Feb 5:1-7.

[2] Cipriani A. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018. Feb 21.

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Pregnancy antidepressant use and offspring outcomes beyond autism?

I'll say one thing for the British Medical Journal (BMJ), they don't seem to be afraid to cover important issues relating to the *possible* "reproductive safety of drugs" [1] as per their publication of yet another paper looking at antidepressant use during pregnancy and offspring outcomes published by Xiaoqin Liu and colleagues [2]. This follows another paper published in the BMJ and covered on this blog a few weeks back (see here).

The specific class of drugs being examined again are, as I mentioned, the antidepressants and based, yet again, on data from one or more of those wonderful Scandinavian population registries in relation to how pregnancy use of antidepressants *might* impact on risk of risk of various psychiatric disorders in offspring. A diagnosis of autism spectrum disorder (AD) has been a primary focus of previous research in this area; particularly the question of whether the medicines themselves or the condition(s) that the medicines are used for (i.e. maternal psychopathology) might be the more important variables related to enhanced offspring risk of autism. The last paper covered on this blog by Rai and colleagues [3] very cautiously suggested that: "The results of all these analyses, which used different assumptions, seemed to be consistent with each other, suggesting that the association between in utero exposure to antidepressants and autism might not be fully explained by confounding." Cautiously...

This time around the net was widened from just looking at autism as an offspring outcome to "overall risk of psychiatric disorders" including: "autism spectrum disorder... mood disorder... neurotic, stress related, and somatoform disorder... behavioural and emotional disorder... and mental retardation." I might add that these are the authors words not mine and diagnoses were based on ICD-10 criteria and codings.

Looking and following some 900,000 children born between 1998 and 2012 in Denmark until 2014, researchers categorised participants according to their pregnancy antidepressant exposure(s): "unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy)" and looked at the frequency of those conditions included for study.

Results: some 2% of children were born to mums who used an antidepressant during pregnancy (n=21,063). Various types of antidepressants were used but the majority were prescribed SSRIs (Selective Serotonin Reuptake Inhibitors) either alone (monotherapy) or in conjunction with other non-SSRI medication.

"We observed increased risks of psychiatric disorders in all three groups of antidepressant users (discontinuation, continuation, and new user groups), compared with the unexposed group." This itself is an important finding but does not yet disentangle whether medicine use or the reason(s) for medicine use might be the more important variable. Then: "we observed an increased risk of psychiatric disorders in children whose mothers continued antidepressant use during pregnancy, compared with mothers who discontinued." Such a statement potentially edges a little closer to some influence of pregnancy antidepressant use on offspring outcomes but, and it is an important but: "These associations could be attributable to the severity of the underlying maternal disorders in combination with in utero antidepressant exposure." In other words, those mums who needed to continue antidepressant use throughout pregnancy probably had to do so because their symptoms either returned or were not controlled properly when medication is not in place. This might imply that more serious maternal psychiatric disorder could be a variable in any enhanced risk of offspring psychiatric disorder.

When it came to looking at specific diagnostic labels for offspring, all but "mental retardation" (I prefer the term learning disability) seemed to be elevated alongside "in utero exposure to antidepressants." The conditions with the highest risk were the mood disorders including diagnoses such as clinical depression and bipolar disorder. Given that antidepressants are typically (but not exclusively) used to treat/manage mood disorders, such a finding of maternal mood disorder potentially transmitting down into offspring mood disorder receives further credence from such results.

The Liu paper and accompanying editorial grapple with the question of whether the *possible* risks from pregnancy use of antidepressants on offspring merit a change to guidance on their use at such a critical time. As I've mentioned on other occasions discussing this topic, antidepressants are not typically just dispensed willy-nilly without appropriate clinical indication. They provide an important service in controlling various types of symptoms; pertinent to the idea that uncontrolled depression during pregnancy for example, can have all-manner of negative outcomes. As all medicines do, yes they may have side-effects but these need to be weighed up against perceived benefits, taking into account any important influence on the developing child. Indeed, the authors note: "any final decision on antidepressant continuation should be individualised and made jointly by health professionals and patients."

And whilst I've mentioned pregnancy antidepressant use and offspring autism risk, yet another review paper enters the scientific fray [4]...

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[1] Nordeng H. et al. Prenatal exposure to antidepressants and increased risk of psychiatric disorders. BMJ. 2017; 358: j3950.

[2] Liu X. et al. Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study. BMJ. 2017; 358: j3668.

[3] Rai. D. et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017; 358: j2811.

[4] Andalib S. et al. Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review. Eur Psychiatry. 2017 Jun 20;45:161-166.

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Antidepressants during pregnancy and autism in offspring (with care)

There are a few topic areas in the quite vast autism research landscape that consistently seem to keep cropping up. The possibility of some kind of *association* between pregnancy antidepressant use and risk of offspring autism is one of those areas (see here) as the results published by Dheeraj Rai and colleagues [1] (open-access) are presented for your attention. I would also draw your attention to an accompanying editorial discussing the Rai findings (see here).

So: "To help to improve the understanding of the association between antidepressant use during pregnancy and autism in offspring, we applied a range of... causal analytical methods on data from a large total population cohort in Stockholm County" was the starting point, as once again one of those very useful Scandinavian registries provided the source study material (indeed, Rai et al are seemingly experts in their analysis of such resources). The added bonus to the Rai study was their attempt to 'unravel' any association between gestational antidepressant exposure and autism from the reason why such medication was being taken in the first place: maternal psychiatric health issues (and whether this variable may in fact account, at least in part, for any association that has previously been identified).

From a starting population approaching three-quarters of a million people, researchers eventually settled on looking at over 250,000 children under 17 years of age (but over 4 years of age "in whom a diagnosis of autism might be less reliable") who were born to over 150,000 mothers. The vast majority of children (239,943 of 254,610) had no history of exposure to antidepressants during pregnancy. The remaining participants were divided up into two groups: one where there was documentation leading to the assumption of exposure to pregnancy antidepressants (n=3342) and one where there was an indication for such exposure ("mothers with a psychiatric disorder") but no recorded use of antidepressants during pregnancy (n=12,325). Researchers summed up how many children were diagnosed with an autism spectrum disorder (ASD) in each group and applied some statistical modelling.

Results: I think it's important to first highlight a statistic that seems to have been missed by many covering the Rai findings: "Of the 238 943 cohort children for whom there was no record of maternal history of psychiatric disorder or antidepressant use during pregnancy, 4889 had autism (2.1%)." That's 2.1% with a diagnosis of autism or ASD; quite a far cry from the 1% [estimate] statistic from just a few years back (at least here in Blighty).

Then: "Exposure to antidepressants during pregnancy was associated with a higher odds of a diagnosis of autism in offspring than exposure to a maternal psychiatric disorder without antidepressants." The authors caution that: "the absolute risk was small, and 4.1% of children exposed to antidepressants in utero had autism compared with 2.9% of those with a maternal history of psychiatric disorder." Further when looking at those children diagnosed with ASD in the groups, authors observed that "autism without intellectual disability" seemed to be over-represented; something also picked up in previous findings from authors on this current paper [2].

Alongside various opinions on these findings (see here for example), the authors caution about the possible meaning of their results. One obviously has to be quite careful when discussing such data to ensure that an important class of medicines is not unduly vilified. No medicine is however without potential side-effects and appropriate clinical decisions and good medicines management [2] is key, particularly when pregnancy is included as variable. The authors talk, for example, about how "if a causal link were robustly established, and if no pregnant women took antidepressants during pregnancy, only 2% of autism cases in this population would be prevented." Alongside they [importantly] mention that antidepressant use during pregnancy is not typically just a 'choice' but rather being clinically indicated: depression does not simply disappear when a woman is pregnant. Interestingly too, they mention about how their data "suggest that there is an increased background risk of autism in children of women with psychiatric conditions, regardless of antidepressant treatment." This follows a trend in other areas of psychiatry (see here for example).

Yet again, the call is further research in this area and, quite a few more investigations into the possible hows-and-whys of any association (with medication use and/or maternal psychiatric presentation) is made. I might also suggest that taking into account other childhood conditions such as attention-deficit hyperactivity disorder (ADHD), potentially over-represented when it comes to a diagnosis of autism or ASD, could be another important step forward in light of other preliminary *associations* being made with pregnancy medication history in mind (see here). This also includes looking at any issues associated with timing of potential exposure and/or dose ("Because of small numbers, we were not able to assess trimester specific or dose response effects.").

Insofar as the suggestion that autism without intellectual (learning) disability might be an important phenotype when it comes to any association, subsequent research in this area seemingly fits in well with increasingly vocal calls [4] to stop using the generic label of autism as a research starting point (see here). Allied to suggestions for more 'bottom-up' research with autism in mind (see here), also coincidentally mentioning "maternal SSRI use during pregnancy" in the context of autism [5], a future research agenda is seemingly emerging. I might also point out that certain sensitivities need to be kept in mind on the basis of suggestions that an 'environmental exposure' might, in whole or part, be *associated* with a particular type(s) of autism.

All such work - present and future - however needs to be done/presented with care, understanding and minus scaremongering, so as not to unduly alarm pregnant mothers, their families or indeed, the physicians providing their care at such a critical time...

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[1] Rai D. et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017; 358: j2811.

[2] Rai D. et al. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ. 2013 Apr 19;346:f2059.

[3] Angelotta C. & Wisner KL. Treating Depression during Pregnancy: Are We Asking the Right Questions? Birth Defects Res. 2017 Jul 17;109(12):879-887.

[4] Waterhouse L. et al. The ASD diagnosis has blocked the discovery of valid biological variation in neurodevelopmental social impairment. Autism Res. 2017 Jul;10(7):1182.

[5] Unwin LM. et al. A "bottom-up" approach to aetiological research in autism spectrum disorders. Front Hum Neurosci. 2013 Sep 19;7:606.

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Is gluten avoidance linked to a lower risk for depression?

I've talked a few times on this blog about how avoiding dietary gluten both within (see here) and outside of (see here) the context of coeliac (celiac) disease, the archetypal 'gluten is baddie' autoimmune condition, might have some pretty interesting effects on some aspects of a person's psychology. Today's post reflects yet more peer-reviewed science suggesting that there may indeed be something to see in this potentially important area; particularly pertinent to the presentation of depression or depressive symptoms.

So, the findings reported by Haley Zylberberg and colleagues [1] based on data from some 22,000 participants taking part in the US 2009-2014 National Health and Nutrition Examination Survey are the source material today. Some background material related to this cohort can be found here. They specifically looked at the "prevalence of depression, insomnia, quality-of-life variables, and psychotropic medication use in CD [coeliac disease] participants and PWAGs [people who avoid gluten] to controls." People who avoid gluten - PWAG - represent a group who don't have a diagnosis of CD but nonetheless similar to those who were diagnosed with CD, reported avoiding dietary gluten.

Results: "Depression was present in 8.2% of controls compared with 3.9% of participants with CD... and 2.9% of PWAGs." Even after adjustment for various confounding variables ("age, sex, race, income, and access to healthcare") those gluten avoiders (without CD) less frequently presented with depression compared with data from controls.

Added to the previous occasions where gluten consumption seems either to be linked to [some] depression or removal of gluten seems to positively impact on depressive symptoms at least for some, this is interesting work. Yes, quite a few more controlled trials are required to examine such relationships between food and mood. Although we can speculate on possible mechanisms [2] we don't really know why there may be an effect from gluten removal, but this is an emerging area of science; particularly in the context of how disruptive/disabling/damaging depression can be to someone.

Bearing in mind the caveats of this blog - no medical or clinical advice is given or intended - please don't assume that I'm advocating gluten removal for anything (unless clinically indicated) on the basis of this or other posts. If in doubt, consult your medical physician.

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[1] Zylberberg HM. et al. Depression and insomnia among individuals with celiac disease or on a gluten-free diet in the USA: results from a national survey. Eur J Gastroenterol Hepatol. 2017 Jun 27.

[2] Pruimboom L. & de Punder K. The opioid effects of gluten exorphins: asymptomatic celiac disease. J Health Popul Nutr. 2015 Nov 24;33:24.

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Antidepressant use in pregnancy and risk of offspring ADHD?

Here we go again. Antidepressant use during pregnancy comes under the spotlight yet again (see here) as per the findings reported by Takoua Boukhris and colleagues [1], this time in connection to risk of offspring diagnosis of attention-deficit hyperactivity disorder (ADHD) following gestational exposure to this class of medicines.

Drawing on data derived from the Quebec Pregnancy/Children Cohort (QPC), researchers set out to examine the "risk of ADHD associated with overall and class-specific antidepressant exposure in utero." I might add that previous data from some of the authors of the Boukhris paper on the QPC has suggested that it is "an excellent tool for the study of the risk and benefit of drug use during the perinatal period" [2].

Following nearly 150,000 live births between 1998 and 2009, researchers looked at the rates of subsequent diagnosis of ADHD alongside the pattern of medication use during pregnancy and other important variables such as "maternal history of depression/anxiety and ADHD." They concluded that: "AD [antidepressant] use during the 2nd and 3rd trimester of pregnancy, specifically tricyclics, is an independent risk factor for ADHD in children above and beyond the risk associated with maternal depression/anxiety or ADHD." Further: "SSRI [Selective serotonin reuptake inhibitors] and SNRI [Serotonin–norepinephrine reuptake inhibitors] use were not associated with increased ADHD risk."

As per the convoluted research history talking about pregnancy antidepressant 'exposure' and possible risk of offspring autism, there are certain caveats and issues worth mentioning. Antidepressant use during pregnancy is not something to be taken lightly as per any calls to 'restrict use' during the special nine months that make us. Such medicines serve an important purpose in controlling some potentially important clinical symptoms; said symptoms do not just dissipate during the special time called pregnancy as per other clinical examples with other labels (see here).  It's also worth pointing out that such observational studies looking at medication use and offspring outcomes are just that - observational. As per the tenet 'correlation is not the same as causation', one has to be a little careful with such data...

That all being said, I do find the Boukhris results to be intriguing on the basis that this is not the first time that an *association* has been talked about in the peer-reviewed science domain [3] and on more than one occasion [4]. Further investigations are perhaps required into the possible mechanism(s) involved in any such relationship between medicine and offspring development, and indeed, whether such connections could potentially invite new intervention options for labels like ADHD? I'm also more than a little interested in the 'medication type' angle to the Boukhris observations not necessarily being the same as that put forward in relation to offspring risk of autism.

And just before you go, it's worth highlighting the findings reported by Viktorin and colleagues [5] looking at pregnancy antidepressant use and intellectual (learning) disability: "After adjustment for confounding factors... the current study did not find evidence of an association between ID and maternal antidepressant medication use during pregnancy."

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[1] Boukhris T. et al. Antidepressant Use in Pregnancy and the Risk of Attention Deficit with or without Hyperactivity Disorder in Children. Paediatr Perinat Epidemiol. 2017 Jun 22.

[2] Bérard A. & Sheehy O. The Quebec Pregnancy Cohort – Prevalence of Medication Use during Gestation and Pregnancy Outcomes. Croy A, ed. PLoS ONE. 2014;9(4):e93870.

[3] Man KKC. et al. Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study. BMJ. 2017 May 31;357:j2350.

[4] Clements CC. et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry. 2015 Jun;20(6):727-34.

[5] Viktorin A. et al. Association of Antidepressant Medication Use During Pregnancy With Intellectual Disability in Offspring. JAMA Psychiatry. 2017 Jul 12.

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Pregnancy exposure to SSRIs and offspring autism risk: debate continues

"It remains unclear whether the association between first trimester SSRI [selective serotonin reuptake inhibitor] exposure and child autism that was present in the case-control studies even after adjustment for MMI [maternal mental illness] is a true association or a product of residual confounding."

So said the results of the systematic review and meta-analysis undertaken by Hilary Brown and colleagues [1] looking at a potentially important association between pregnancy use of a class of medicines typically used as antidepressants (albeit with some caveats [2]) and risk of offspring autism. This topic has previously received some airtime on this blog (see here and see here) and specifically, how maternal mental health - as per the question 'why were mothers taking SSRIs during pregancy?' - might be a rather large confounding variable affecting any possible correlation.

Unfortunately even with the Brown paper, the debates will continue as to whether the SSRI-offspring autism correlation is a 'true' correlation or not. Based on the results of 6 studies - "4 case-control studies and 2 cohort studies" - where MMI was adjusted for/restricted to, authors reported some interesting trends. So in their meta-analysis of the data where results from case-control studies were adjusted for a potential impact from MMI, researchers observed that "first trimester exposure remained statistically significant." In "MMI-restricted analyses" covering the same study type, the collected studies did not show any connection between pregnancy SSRI use and offspring autism during either the first trimester or 'any time during pregnancy'. Similar results were found in the cohort studies included in the Brown paper (although both first trimester and 'any point during pregnancy' SSRI use both showed significant correlations to offspring autism in adjusted studies). I might also add that the Brown meta-analysis on this topic is not the only recent addition to the peer-reviewed literature [3]; indeed, there are several [4] others.

"Future studies require robust measurement of MMI prior to and during pregnancy" said Brown et al. I would agree with this sentiment added to the caveat that we may never truly know whether there is a definitive connection between pregnancy SSRI use and offspring autism risk on the basis of observational studies alone. Yes, I know it is unethical to withhold treatment such as SSRIs when clinically indicated even during pregnancy and so investigations utilising this kind of 'interventionist' study design are not likely to be undertaken anytime soon. But it does strike me that we could do quite a bit more modelling any potential effects (or not) in animal studies for example, as per some investigations with fish a while back (see here) as a start.

And finally, although it is not my place to give clinical or medical advice on this blog, I should point out that much like investigations on another medicine prescribed during pregnancy potentially linked to offspring outcomes (see here), SSRIs are not generally given willy-nilly to pregnant women; there are very valid reasons for managing mum's psychiatric health particularly during pregnancy. If anyone is in doubt, please consult your doctor (and not just Dr Google).

To close, before 'fake news' there was The Day Today (and they did it oh so well)...

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[1] Brown HK. et al. The Association Between Antenatal Exposure to Selective Serotonin Reuptake Inhibitors and Autism: A Systematic Review and Meta-Analysis. J Clin Psychiatry. 2017 Jan;78(1):e48-e58.

[2] Jakobsen JC. et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC Psychiatry. 2017; 17: 58.

[3] Kaplan YC. et al. Prenatal selective serotonin reuptake inhibitor use and the risk of autism spectrum disorder in children: A systematic review and meta-analysis. Reprod Toxicol. 2016 Dec;66:31-43.

[4] Kobayashi T. et al. Autism spectrum disorder and prenatal exposure to selective serotonin reuptake inhibitors: A systematic review and meta-analysis. Reprod Toxicol. 2016 Oct;65:170-178.

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Brown HK, Hussain-Shamsy N, Lunsky Y, Dennis CE, & Vigod SN (2017). The Association Between Antenatal Exposure to Selective Serotonin Reuptake Inhibitors and Autism: A Systematic Review and Meta-Analysis. The Journal of clinical psychiatry, 78 (1) PMID: 28129495

Add-on nutraceuticals for depression?

It came as no surprise to me that the systematic review and meta-analysis article by Jerome Sarris and colleagues [1] found what it did in relation to the use of [certain] adjunctive (add-on) nutraceuticals alongside antidepressants to reduce depressive symptoms: some of them might actually be clinically useful.

With no medical or clinical advice given or intended, the authors report that "adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants" might be something to consider "for improving inadequate response to antidepressants." Dr Sarris was one among many authors who contributed to the 'personal view' paper titled: 'Nutritional medicine as mainstream in psychiatry' [2] which was also covered a while back on this blog (see here). This latest addition to that and other opinions [3] which covered the peer-reviewed literature on a variety of nutrients also found something of a mixed bag of results for various other compounds including the aromatic amino acid tryptophan, zinc, folic acid and vitamin C.

Quite a bit more science needs to be done in this area, not least around the hows and whys that the various preparations might exert some effect. Vitamin D has of course been covered quite a bit on this blog in relation to something like depression (see here for example) so that particular nutraceutical might already have a research head start compared to others. I'm also minded to suggest that the involvement of something like SAMe (S-adenosylmethionine) as an add-on treatment might also imply a role for epigenetic variables in relation to at least some depression [4]. And then there is the question of who might be best responders to such nutraceutical use which implies heterogeneity and possible plural depressions...

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[1] Sarris J. et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. American Journal of Psychiatry. 2016. April 26.

[2] Sarris J. et al. Nutritional medicine as mainstream in psychiatry. Lancet Psychiatry. 2015 Mar;2(3):271-4.

[3] Sarris J. et al. International Society for Nutritional Psychiatry Research consensus position statement: nutritional medicine in modern psychiatry. World Psychiatry. 2015 Oct;14(3):370-1.

[4] McGowan PO. & Kato T. Epigenetics in mood disorders. Environ Health Prev Med. 2008 Jan;13(1):16-24.

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Sarris J, Murphy J, Mischoulon D, Papakostas GI, Fava M, Berk M, & Ng CH (2016). Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. The American journal of psychiatry PMID: 27113121

Pendulum swings... prenatal antidepressant exposure not linked to autism or ADHD

"Multiple studies have examined the risk of prenatal antidepressant exposure and risk for autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD), with inconsistent results."

And...

"These results suggest that prior reports of association between prenatal antidepressant exposure and neurodevelopmental disease are likely to represent a false-positive finding, which may arise in part through confounding by indication."

'These results' refers to the findings reported by Castro and colleagues [1] (open-access available here) who looked at the records of over 1200 children diagnosed with ASD and ~1700 children diagnosed with ADHD compared with over 3400 and 3700 controls respectively with regards to antidepressant exposure during pregnancy and maternal antidepressant use before pregnancy. Based on exposures identified "using e-prescribing data in the EHR [electronic health records], both inpatient and outpatient, which record number of pills, frequency and refill number, allowing calculation of exposure period" researchers were, with reasonable confidence, able to test the idea that a diagnosis of ASD or ADHD might be elevated following prenatal exposure to said pharmaceutics.

The headline that most media discussing this study picked up on was the lack of any significant association between antidepressant use during pregnancy and risk of offspring autism or ADHD. This finding kinda contrasts with other recent independent reports that have been covered on this blog (see here). Indeed the authors - including one Isaac Kohane (see here) - suggest that their results, bearing in mind certain limitations, highlight how 'false-positive' might indeed be a good description of some of the previous data in this area.

But just before any sweeping generalisations are made about this class of pharmaceutic being 'off the hook' there were some other potentially important findings also reported by Castro et al. To quote once again: "For both ASD and ADHD, pre-pregnancy antidepressant use was associated with greater risk, even after adjustment for maternal major depression." The risk reported was significant insofar as what it might mean for offspring autism and/or ADHD and also how "the requirement for maternal antidepressant treatment, rather than the medication itself, may be associated with risk for neurodevelopmental disorders in offspring".

As I've discussed before, the idea that antidepressant use during pregnancy might be linked to offspring developmental outcomes is a complicated area. That such medicines use is not generally entered into lightly is something to bear in mind given what depression can do to a person and those around them. I cannot readily account for the discrepancy between these and other reports on this topic outside of the idea that the question of a connection or not may not be as simple as 'yes' or 'no' but rather a slightly more convoluted story where genetics and other more 'environmental' factors might play some role. The idea that there may be specific phenotypes of autism associated with such medication use has received a boost in other independent studies [2] looking at other medicines. I suppose such confusion kinda sums up autism research when it comes to questions of such exposure and the range of pharmaceutics that have been correlated with offspring risk (see here and see here).

Music: Björk - It's Oh So Quiet. Shhh.

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[1] Castro VM. et al. Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Transl Psychiatry. 2016 Jan 5;6:e708.

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Castro VM, Kong SW, Clements CC, Brady R, Kaimal AJ, Doyle AE, Robinson EB, Churchill SE, Kohane IS, & Perlis RH (2016). Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Translational psychiatry, 6 PMID: 26731445

Pregnancy antidepressant use and risk of offspring autism (again)

"Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD [autism spectrum disorder] in children, even after considering maternal depression."

That was the conclusion reported in the study by Takoua Boukhris and colleagues [1] dealing with a topic which has previously graced the autism research landscape (see here and see here). Detailing the results of a "register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort" covering data on all pregnancies in Québec (Canada) between 1998 and 2009 (N=145 456 singleton full-term infants born alive and whose mothers were "covered by the Régie de l’assurance maladie du Québec drug plan for at least 12 months before and during pregnancy"), the Boukhris results have created quite the media stir.

Among the 140,000+ infants followed up, just over 1000 were eventually diagnosed with an autism spectrum disorder (ASD) equating to 0.7% of the population. When researchers looked at those who were prenatally exposed to antidepressants specifically during the second or third trimester of pregnancy, the rate of ASD was calculated at 1.2%. When also controlling for potentially confounding variables such as a maternal history of depression, the elevated risk of offspring autism persisted. Ergo, there may be more to see when it comes to antidepressant use during pregnancy and offspring developmental outcomes. I might also direct readers to an editorial discussing the findings [2].

Most of the media on this latest paper have been quite sensible about the findings. They've for example, pointed out that other research studies have reported slightly less in the way of any connection between pregnancy antidepressant use and offspring autism (see here) as well as putting the results into some context with the idea of what 'elevated risk' might actually translate into (see here). That also antidepressant use during pregnancy is not normally entered into lightly without good reason is something else that I'd bring into proceedings as per other research talking about other pregnancy medication use and potentially elevated risk to offspring outcomes (see here).

The authors do suggest that more research is required to build on their findings and "to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy." I would agree that we do need more data on this possible association (including that from animal models and related studies) in order to ascertain whether specific medicine formulations might be more strongly involved and onwards the possible mechanism(s) of effect. I'm not necessarily sold on the idea that serotonin chemistry is specifically the be-all-and-end-all of any effect on the unborn child given what we are starting to realise about the wide-ranging effects of various medicines outside of that listed on the package insert (see here). I am willing however to entertain the idea that the further reaches of tryptophan metabolism might eventually come into the frame (see here). We await further studies.

Music now, and with the imminent launch of a certain Russian Soyuz rocket, a song for Tim...

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[1] Boukhris T. et al. Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children. JAMA Pediatrics. 2015. Dec 14.

[2] King BH. Assessing Risk of Autism Spectrum Disorder in Children After Antidepressant Use During Pregnancy. JAMA Pediatrics. Dec 14.

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Boukhris, T., Sheehy, O., Mottron, L., & Bérard, A. (2015). Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children JAMA Pediatrics DOI: 10.1001/jamapediatrics.2015.3356

MoBa does prenatal antidepressant use and offspring anxiety

MoBa, otherwise known as the Norwegian Mother and Child Cohort Study, has found it's way onto this blog a few times over the years. If it's not to do with results concerning prenatal paracetamol (acetaminophen) exposure and possible offspring neurodevelopmental outcomes (see here), it's about confirming that bowel issues are indeed over-represented in cases of autism (see here) and lots more besides.

We can now add the results from Ragnhild Eek Brandlistuen and colleagues [1] (open-access) to the MoBa tally and the intriguing suggestion that: "Prenatal exposure to antidepressants was associated with increased levels of anxiety symptoms in 3 year old children after adjusting for maternal familial effects and confounding by indication (i.e. maternal depression)."

Based on starting data for over 20,000 siblings, researchers asked mothers "to report antidepressant use at gestational weeks 17 and 30 and 6 months post-partum" as well as measuring externalizing and internalizing problems in offspring at 18 and 36 months of age using the Child Behaviour Checklist for Ages 2–3 via 'mother-reporting'. Antidepressants were categorised according to the Anatomical Therapeutic Chemical (ATC) Classification System, code N06A covering the full spectrum of this class of pharmaceutics. Externalising and internalising problems included an array of behaviours including attention and aggressive issues through to anxiety and 'emotional reactivity' present in offspring. I might add that authors also asked quite a few questions about maternal mental health too alongside looking at other classes of medication and whether or not mothers reported smoking or alcohol consumption at specific points in pregnancy.

With the application of some statistical wizardry, researchers reported that: "Prenatal exposure to antidepressants was associated with increased levels of internalizing behaviour problems in the adjusted analyses at 36 months for the subdomain of anxiety." As per the coverage of the Brandlistuen paper on the MoBa website (see here) "The study also found evidence that maternal depression was independently associated with child behaviour problems. There was however a stronger association between antidepressant exposure and child behaviour problems than between depression and child behaviour problems." The use of sibling pairs also adjusted "for shared genetic and familial confounding." The authors speculate on the hows and whys of their results but I'm venturing no further into this area based on the current data.

One of the first thoughts that ran through my mind on reading the Brandlistuen paper was the issue of prenatal antidepressant use and risk of offspring autism - sorry, autistic traits, that has been previously discussed on this blog (see here). Accepting that anxiety and autism might not be as far apart as one might first imagine (see here), the idea that maternal depression or the use of pharmacotherapy to treat/manage said depression might have some important effects for offspring development is gaining traction.

One does however have to be a little cautious about the possibility of a link between prenatal antidepressant use and/or depressive disorder and offspring anxiety given some potentially important methodological limitations discussed by the authors of the current study. The use of self-report is one possible issue, particularly when it comes to assessing medicine use and the fact that the authors "could not take the dose of antidepressants into consideration because it was not reported." With the idea that 'the dose makes the poison' firmly in mind, I would suggest that further investigation in this area is warranted.

Finally and perhaps most importantly, there is the question about what action if any is needed following these latest findings. "Potential long-term effects of medication and untreated maternal mental disease should be considered when assessing the benefits and risks of antidepressant use during pregnancy." I would agree with those sentiments, particularly given that antidepressants are not normally dispensed without appropriate clinical indication and that "in the case of severe depression, medical treatment may be necessary." It sounds to me like we have another pregnancy valproate use dilemma on our hands.

Music: Happy Mondays - Hallelujah. Particularly apt given the general election results today and the Happy Monday connection...

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[1] Brandlistuen RE. et al. Behavioural effects of fetal antidepressant exposure in a Norwegian cohort of discordant siblings. Int. J. Epidemiol. 2015. April 14.

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Brandlistuen, R., Ystrom, E., Eberhard-Gran, M., Nulman, I., Koren, G., & Nordeng, H. (2015). Behavioural effects of fetal antidepressant exposure in a Norwegian cohort of discordant siblings International Journal of Epidemiology DOI: 10.1093/ije/dyv030