Dementia advice, Antidepressants, Transplant organs, Vaginal seeding

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INSIDE HEALTH

Programme 9. – Dementia advice, Antidepressants, Transplant organs, Vaginal seeding

TX:  08.03.16  2100-2130

PRESENTER:  MARK PORTER

PRODUCER:  FIONA HILL

Porter

Coming up today:

Antidepressants – most of the debate surrounding these drugs in recent years has centred on if, and when, to start them in people with depression. But what happens at the other end of therapy when you’re better? How do you stop them?

Clip – Kendrick

A rough guide is if you’ve been on the medicine for some weeks then you need some days to come off them.  If you’ve been on them for some months you probably need a few weeks to come off them.  And if you’ve been on them for years you probably need some months to come off them.  So the advice is that we should taper treatment and tailor that to the length of treatment that somebody’s had.

Porter

Transplants – I meet a team in Oxford developing a novel approach to tackling the critical shortage of donor organs. A shortage which means over a thousand people – adults and children – die every year while on the waiting list for the transplant that could have saved them.

Clip

Porter

So looking at the machine in front of us, it’s the size of a large trunk and on the right the obvious thing is there’s a box effectively with a liver in it with lots of pipes with blood coming out.

Nasralla

If I just open this box for you inside here we’ve got a liver.

Porter

Nice and pink.

Nasralla

Perhaps the deceptive thing about the livers on this machine is that regardless of whether they’re good or bad they all seem to look beautiful.  And this one also does.

Porter

More from that lab in Oxford later in the programme, but first - dementia. And this week’s announcement that raising the issue with people as young as 40 is to be a cornerstone of the Prime Minister’s Challenge on Dementia – an initiative which aims, by 2020, to make England the best country in the world for dementia care.  GP Dr Margaret McCartney is in our Glasgow studio – Margaret 40 is young!

McCartney

It’s very young and where is the evidence Mark?  This is what I ask myself.  We’re asked to be aware of so many different things about our health now and in the future about our risk factors and what I really want to know is does this work and what are the harms.  And neither of those two questions have been answered satisfactorily.

Porter

Margaret, the thing that struck me about this was that there didn’t seem to be a lot of substance, I wasn’t sure exactly what a surgery – my surgery’s in England so I’m going to have to implement this – and I didn’t know exactly what we were going to be asked to do.

McCartney

Well there were lots and lots of headlines and there were many confusing headlines, some of which seem to suggest that doctors and nurses doing these checks would be asked to screen people, ask people whether or not they had memory problems that could be indicative of dementia or not.  But that doesn’t seem to be the case.  What Public Health England are now saying is that this is a pilot, so only going to happen in some areas.  In the very early stages of development and something which will be developed over time.  They do also say that it’s going to be about awareness raising, education and discussion about risk.  But what I really want to know is what are the benefits, what are the harms, is this proven to work, is this a worthwhile intervention to get health professionals to spend time on and patients or citizens who are going to become patients once they’ve walked into the room to have this consultation, what are they going to make of it, is it going to be useful for them.

Porter

And what does existing evidence tell us about that, I mean presumably they’ve come up with this initiative based on some evidence?

McCartney

Well not that I can find.  So we know that there are lots of things that are risk factors for future memory problems and dementia but they tend to be risk factors that we’re already thinking about anyway, for example, to think about cardiovascular risk, risk of obesity, so we’re talking about things like exercise, smoking and a good diet.  We have heard this before, this is not new, you could perhaps think about things like social integration when you talk about memory or protecting your memory in the future, doing things, being active but again these are all things that are part of a normal healthy lifestyle anyway and I’m not aware of any studies that say that giving more advice at the age of 40 is going to prevent dementia in the future.  And instead of running into doing a big programme, without much evidence behind it, do a randomised control trial, not even a pilot, because I’m slightly worried that no matter what the pilot says it’s going to happen anyway and there are always harms and I’m worried that we’re going to make a lot of people alarmed or concerned or afraid for the future when we should be giving people that make them feel a little bit more in control rather than things being more out of their control.

Porter

Thank you for now Margaret.  And just to be reiterate, this initiative applies only to England with the rest of the UK having no plans to follow suit as far as we can ascertain. And there are more details on our website. Where you can also find out how to get in touch.

This Inside Health listener emailed in with a query about antidepressants:

Listener - Read

Please could you do something about when to come off antidepressants? It’s an important topic that must affect a lot people. Fortunately they worked well for my depression and I am a lot better now, but I don’t have the sense about the right amount of time to be taking them.  What’s the latest thinking on the subject?

Porter

Well, I know just the man to ask. Tony Kendrick’s been a GP for many years and he’s now a   Professor of Primary Care at the University of Southampton.

Kendrick

Ever since the early 1990s the number of prescriptions we’ve been giving out of antidepressants has increased year on year.  And this is not peculiar to England or the UK, it’s the same in all Western countries where it’s been looked at.  And our own research looked at three possible reasons for this.  One was were we diagnosing more and more people over time with depression?  Secondly, having diagnosed them were we treating a great proportion of them with antidepressants?  Or thirdly was each person diagnosed being treated for longer which meant that they would get more prescriptions?  And our research shows that it’s largely the third cause.  GPs are diagnosing a relatively low number of people each year with depression, about 1% of people.  They treat around three quarters of them with antidepressants, around 70%, but the number of prescriptions they’ve been giving to people has doubled over a 10 year period, from 2003 to 2013.  So the rise in the number of prescriptions has been due to longer treatment and it’s giving some cause for concern now because the health survey for England showed that antidepressants were being taken by more than one in 10 adults in England, 11% of adults, more women than men and that was comparable to levels of drugs taken for high blood pressure or cholesterol.  And it was really questionable as to whether we should have such a high proportion of adults on antidepressants.

Porter

Well let’s look at somebody presenting for the first time with their first episode of depression, they may have tried talking therapies, they’ve ended up on medicines, they’re feeling better.  How long should they be taking the tablets for?  First of all, if they feel better are they better?

Kendrick

Yes if they feel better they’re certainly better but we do have evidence that if they stop treatment too soon they have a higher risk of relapse.  And the evidence suggests, the best evidence and NICE guidelines, suggest that people should stay on treatment for at least six months after they’ve improved.  Most people take some weeks or months to improve, so in practice that means people should probably be on treatment for the first episode for somewhere between nine and 12 months.

Porter

Okay let’s assume that they’re nine months in, we decide to stop therapy, do we need to wean people off?

Kendrick

We do indeed need to wean people off.  Again there’s evidence that shows that if people stop treatment suddenly they can get withdrawal symptoms.  Perhaps one to two-thirds of people will get some withdrawal symptoms but they’re usually mild and can be controlled if the person is weaned off the medicine.  And a rough guide is if you’ve been on the medicine for some weeks then you need some days to come off them.  If you’ve been on them for some months you probably need a few weeks to come off them.  And if you’ve been on them for years you probably need some months to come off them.  So the advice is that we should taper treatment and tailor that to the length of treatment that somebody’s had.  And that really needs to be done in discussion with your GP or with the nurse practitioner that has prescribed the treatment for you.

Porter

One of the complications of withdrawing antidepressant therapy from someone who may well be better is that those withdrawal effects that you refer to, it’s very easy to confuse that with the return of the symptoms, of their anxiety, of their depression.

Kendrick

It is, yes, one of the commoner withdrawal symptoms is anxiety along with headaches and dizziness and some people get some odd sensory symptoms, for example pins and needles or electric shock type feelings that people call brain zaps.  But certainly anxiety is one of the symptoms and also low mood or swinging mood and lethargy.  So without being informed of that people often think, and this certainly happens if they try and take themselves off the medication, they often think that the original problem – depression and anxiety that they had to take the antidepressant for – is returning.  When in fact it’s probably withdrawal symptoms which should be temporary.

Porter

Looking at the people who are taking antidepressants long term at the moment in the UK I suspect they could broadly divided into two groups, of those who are on them long term appropriately, they may have lots of relapses and it’s a decision to leave them on their medication, there’s another group who are on them inappropriately.  How do we spot the inappropriate ones?

Kendrick

Well I think first of all everyone should be reviewed by their GP or the nurse who’s treating them initially at the end of the treatment for the first episode and a decision made, in discussion with the patient, about whether treatment should be continued at that point.  NICE guidelines suggest that treatment might be continued, so-called maintenance treatment, if the person is at high risk of recurrence.  Now that might mean because they’ve had recurrences before.  It might also be that they still have some residual symptoms of depression which are not completely recovered.  Or thirdly, if they’ve got ongoing difficulties in their lives, they’re going through very hard times or they’ve had recent bad life events then that might be a reason to continue them.  And then in the first instance probably continue them for two years, after which time they should be reviewed again.  The problem we have at the moment is that once people are on long term antidepressants, and around half the people who are on them now have been on them for more than two years, they might be on repeat prescriptions and they may not even see the GP from month to month, and if they’re not being reviewed then it’s hard to know if they should really be continuing with them.

Porter

Looking at that group in particular, besides the obvious resource issues, the fact that a patient is possibly taking a medicine they don’t need, is there any harm that could be done to that individual from taking these drugs for too long?

Kendrick

Yes.  Over time more and more side effects have emerged from the antidepressants, the commonest one – selective serotonin reuptake inhibitors, the SSRIs, the Prozac type drugs – those drugs have been found to cause a number of side effects potentially.  Quite commonly you get weight gain over time, you can get sleep disturbances, you can get interference with your libido or your sexual performance.  And then more worryingly in more recent years we’ve recognised that they can cause bleeding, particularly in combination with other drugs which have a tendency to cause bleeding such as anti-inflammatory drugs which are used very commonly for arthritis.  So there are a number of problems that people can get.  But there’s also the issue of a sense of inadequacy that some people feel, that they’re not themselves unless they take a tablet and that they must take a tablet or a capsule every day to stay well, when in fact they probably could, many of them, manage without medication.

Porter

The difficult thing for both the individual and their doctor I suppose is that depression can be – well it is, it’s a terrible condition and once you’ve been through it once, twice, maybe three, four, five times you can understand people wanting to do whatever they can to stop it coming back.  I mean do you think we tend to err on the side of caution on both sides of the consulting desk, is that a factor?

Kendrick

I think so yes and I know personally from having been depressed in the past myself, it’s far from normal sadness, it’s a terrible condition for many people.  And antidepressants have certainly been life saving for many people and I certainly don’t think that people should stop their treatment suddenly or without advice.

Porter

Professor Tony Kendrick.  And you will find a link to the latest guidance on antidepressant use on our website.

There are currently over 7,000 people in the UK on the waiting list for a transplant – around 1200 of whom will never get the organ they need because of a shortage of donors. There simply aren’t enough kidneys, livers, heart and lungs to go round and the situation is getting worse.

The shortage has forced the transplant community to consider using organs that aren’t quite as perfect as they would like – poorer quality, older or damaged ones are now being considered when they would have been rejected in the past.

I went to the Oxford Transplant Centre to meet surgeon Rutger Ploeg. He’s Professor of Transplant Biology at the University of Oxford and part of a team pioneering a radical new approach to looking after and assessing donor organs that should improve the number available for the thousands of people waiting for them.

Ploeg

Because of this enormous increase in demand we have tended to accept many more older donor organs than we used to and we also are now accepting, what we call, higher risk donor organs.  What does higher risk mean?  Well a medical history which maybe 20 years ago we would have said no we are not going to transplant that kidney because for example the patient had significant hypertension, not well regulated and now because of the lack of donor organs we will accept those kidneys and transplant them.  And the good point about the story is that there’s still a lot of success.

Porter

Once the organ is removed from the donor how long have you got – I mean let’s use an example of a kidney?

Ploeg

Once you remove the organs and you preserve them, which means basically right now that we cold store them because – like you do with your refrigerator when you want to keep something healthy you have to have your refrigerator.  So we cool them down to about five degrees and then we can transplant them and then it depends on the organ and the age of the organ, so for example kidneys we would like to transplant within 12-18 hours but sometimes we have to accept 20 hours or over.  Livers predominantly within 12 hours.  Heart is very short because the heart will not function beyond five, five-six hours, so it has to be transplanted within four hours.  Lungs are a little bit more amenable and you can use those lungs up to – well depending on the condition between four and eight hours.

Porter

How often, looking at transplants across the board, do you get a problem caused solely by the fact that the organ’s not of good enough quality?

Ploeg

I think as a rough figure, we have about 500 kidneys per year which we decline and not use because of either uncertainty or because we think this is too risky to transplant.  That of course then introduced the next step – can we somehow repair these organs which would be the ideal way because it’s such a waste isn’t it.  So there’s consent, there’s an organ on the table but we can’t use it because it just doesn’t do what we think it should do.  So that’s why we have developed some technologies – can we imitate the normal physiological situation, so going away from cold to warm, because we’re all warm, we’re all living at 37 degrees.  So we have to find now with miniaturised technology, pumps, which will allow us actually to put an organ on a pump and see whether we can actually assess and test the organ for so many hours.

Porter

And how many hours do you think you’ll be able to do that for?

Ploeg

Well my colleague, Peter Friend in Oxford, has developed, together with his colleague Constantin Coussios, who’s a bioengineer, a device which is now a liver machine and hopefully we’ll go down and show it to you, which now has been able to a normothermically perfuse the liver successfully for 24 hours.  And 24 hours is a very, very good timespan because it will really allow you to assess but also condition and repair.

Porter

I’m intrigued as to how you would condition or repair an organ in such a short time, you’ve got 24 hours and in it’s in a machine, what sort of things can you do or what sort of things have you done?

Ploeg

Well what we know from brain death that it causes an enormous acute inflammatory response, that response will affect every organ.  When we then take that organ out we add with the cold storage additional injury which then starts its rapid decline.  If we, however, take it out and put it again on normothermic perfusion it will allow us to assess it and repair by oxygenating it and may be substituting it with those substances which we think are helpful to repair.  To give you an idea:  inflammatory markers will come up within 20 minutes after an event.  We’ve done some very interesting experiments looking at certain compounds which could may be down regulate that response and therefore maybe, let’s say, subdue the inflammatory response at a lower level which could be better for the organs as they may be less injured.

Porter

Your research is obviously ongoing but this is a step change in thinking, do you think this is the way forward?

Ploeg

I think we all think so, of course there’s other groups in the consortium who collaborate on this.  I think it’s a step change because for the first time with this better technology it allows us to go back to normal physiology, as normal as you can be and then selectively try to tackle and target interventions to what an organ may need.  And of course organs have different needs because a kidney has a different function from the liver or the lung.  So each organ might need a different treatment.

Porter

So can we go and have a look at one of these machines in action?

Ploeg

Yes I think we have a discarded liver which was not usable for transplantation which we put on the machine last night and David Nasralla, who’s one of our DPhil students, he’s very happy to show us the machine and explain a little bit what we’re doing.

Nasralla

So my name is David Nasralla and I’m a clinical research fellow in transplant surgery at the Oxford Transplant Centre. 

This machine in front of us is what’s known as a Normothermic Liver Perfusion device, which means it preserves the liver at normal body temperature, so to keep it in a functioning physiological state.  What the whole transplant community has been trying to find is a way to increase the number of livers that could be made transplantable and that’s exactly where normothermic liver perfusion comes in.  So there’s lots of animal studies that have suggested that this could improve the quality of organs for transplant and we’ve finally got to the point where we’re now running a large clinical trial looking at it.

Porter

So looking at the machine in front of us, it’s the size of a large trunk and on the right the obvious thing is there’s a box, effectively, with a liver in it, with lots of pipes with blood coming in.

Nasralla

If I just open this box for you, inside here we’ve got a liver.

Porter

Nice and pink.

Nasralla

Perhaps the deceptive thing about the livers on this machine is that regardless of whether they’re good or bad they all seem to look beautiful and this one also does.  This is from a relatively young donor and it’s been on the machine for just over 24 hours now.  This liver was deemed not useable for various reasons, so we’ve brought it back here to see if we can resuscitate it.  There’s two blood inflows into the liver, the blood goes in through the hepatic artery, which is this small vessel here and also through this large vein here called the portal vein, so the portal vein drains the whole of your bowel into the liver.  And then the blood that comes out of the liver comes out through this vessel that goes through the back of the liver called the inferior vena cava.  And what we’ve got is the blood goes into the liver through artery and the portal vein, goes in, perfuses the organ and you can see it’s nice and pink and soft and then comes out here through the vena cava.  That noise you just heard, you’ll hear it again, that noise is the sound of the liver measuring the bile that’s being produced.  So one parameter we can use to tell if the liver’s working is whether it’s producing bile.

Porter

So you’re not just keeping it warm and comfortable, if you like, in this machine, you’re actually analysing its function.

Nasralla

Exactly, we’re trying to provide the ideal physiological conditions that you’d find in your body, for example.  For many of these livers we actually see their function improve on this machine, relative to how they are in the donor because a donor, by their very nature, is not very well, so often the conditions in the donor aren’t optimised.  And here you can actually often see an improvement compared to that.

Porter

So potentially if this was to be adopted you could repair the liver surgically, you could operate on it before you put it into the recipient.

Nasralla

You could repair it physically by directly intervening but also this offers a medium by which you could intervene therapeutically.  And there’s now a huge mushrooming of interest in this about trying to use this device to try and give stem cells or give defatting agents, to remove the fat from livers, because fatty livers are the primary cause that they don’t function.  But a lot of people want to try and use this technology to intervene therapeutically to try and improve the organ further.

Porter

Clinical Research Fellow David Nasralla, who works with Professor Ploeg at the Churchill Hospital in Oxford.  And it not just donor livers that are being evaluated in these normothermic conditions, researchers are testing kidneys and other organs too.

Now if the idea of livers connected to machines makes you a little squeamish then you may struggle with what’s coming next. Vaginal seeding – smearing babies born by caesarean with secretions from their mother’s vagina, so they pick up the same micro-organisms that they would have had had they been born naturally.

This initial inoculation helps determine the make-up of the “friendly bacteria”, or microbiota, that live in the child’s bowel, which in turn has been linked to health issues ranging from their propensity to develop allergies, to how their metabolism works.

Frederique Rattue had her first three children naturally and was disappointed to learn that she would need a caesarean section to deliver her fourth. So she set out to make it as close – at least microbiologically - to a natural birth as possible.

Rattue

My wonderful midwife recommended that I watch this documentary called Micro Birth.  And in this documentary it’s really well explained what happens at birth and this transfer of bacteria to the baby from the mum.  And so that was my inspiration, I thought well this is such a simple process to do for myself and my baby.

Porter

So what did it involve?

Rattue

What it involves is a piece of sterile gauze, folded a bit like a tampon, and inserted into the mother’s vagina for an hour before the C section.  That means that this gauze will be colonised by the bacteria from the vagina and then this is placed into a sterile storage bag and once the baby’s born this gauze is simply swabbed all over his face and the rest of his body to seed those bacteria that he’s missed out.

Porter

Was it reassuring that you’d done this, that you’d given your son a good start?

Rattue

Yeah absolutely, it’s a fact that babies who are born naturally have a wider spectrum of microbiota compared to babies born by C section, so I really wanted to restore this balance for him and to set him up for life and his immunity.  And I just thought well it’s really unlikely to cause much harm but it really might do some good, so in my mind I truly believe that I’ve done the right thing for him.

Porter

What’s his name?

Rattue

It’s Jago.

Porter

And how old’s Jago now?

Rattue

He’s one.

Porter

He’s following his brother’s footsteps is he?

Rattue

Absolutely, yeah, he’s just as healthy, no problem, nothing, just exactly what I wanted.

Porter

Frederique Rattue, mother of Jago. Well Dr Margaret McCartney has been looking at the evidence behind vaginal seeding. Margaret, the theory sounds great but is there any evidence that it actually benefits the child?

McCartney

The theory is fantastic, so it’s long been recognised that there are population effects depending on how you were born.  So if you look at thousands and thousands of children born by caesarean section compared to children born by vaginal birth there’s a difference in how many children later on get certain diseases.  We’re talking about things like allergy, asthma, obesity, inflammatory bowel disease – they’re small differences, they’re not enormous but when you get enough children together born by different routes you begin to see a difference between the two populations.  So the question is:  would vaginal seeding change the risk for the children who had caesarean section rather than vaginal birth?

Porter

And the theory is that microorganisms picked up during birth, as you travel down your mother’s vagina, might account for the difference, we don’t know for sure but it might account for the difference in the rates of those diseases between babies born by caesarean and normal?

McCartney

Yes, that’s as far as we’ve got I think with the research just now.  One of the theories is could the difference be explained by the different microbiome with the different groups of children, could children born by caesarean section not picking up these bugs from the mother’s vagina be different in some way from the children born vaginally.  And the next question is:  Could you change that back by doing this vaginal seeding?

Porter

Right, what does the evidence tell us about whether vaginal seeding works?

McCartney

Well this is kind of where the evidence begins to run out.  So there has been a study published recently in one of the nature journals which begins to start to answer some of these questions.  They looked at very small numbers of children, it has to be said, four babies born by caesarean section were immediately after birth swabbed with vaginal fluid from their mother, on their mouth, their face and the rest of their body.  And then the researchers did serial swabs every few days for the first month of that child’s life.  And they found that the bugs on the child’s body born by caesarean section but swabbed with their mother’s fluid were very similar to the children that had been born by a vaginal birth.  So it does seem that you can make an alteration that puts these children back to where they would have been had they been born vaginally.

Porter

So in theory it might work but that doesn’t mean that it will – that it’s responsible for any protective effects.

McCartney

Totally, so this was only four babies first of all, so a very small study.  But then we don’t know what the actual effect of that is in real life.  So there are a few jumps that we’re making here in terms of what causes the difference between these two groups and then will this make a difference.  So we don’t know and that’s where the evidence runs out.  And it’s worth saying that these are small differences between big groups of children in terms of disease risk in later life.  So I think you would have to do really big studies to know the difference.  And what I would really hate is for women to feel so guilty as the result of having a caesarean section that they felt driven to do something that perhaps they might not have done had they had better evidence about it.  The mothers in this study that was just published were checked for any harmful bacteria they could be having, for example streptococcus B that can cause problems with births.  So again there are lots and lots of questions over it and this was done in a proper scientific manner, so I think there are lots of question marks over it.  However, I think it is a really important question and is worthy of a lot of future study.

Porter

We must leave it there, thank you very much Margaret. Just time to tell you about next week when I will be taking a closer look at recent developments in asthma and questioning this paradox – how can asthma be over-diagnosed, yet undertreated? Join me next Tuesday to find out.