Why Don't Antiseizure Medications Work for Everyone? - Graeme Sills, PhD, University of Glasgow, UK
How do we reduce the 30% of people who have uncontrollable seizures? Graeme Sills, PhD, explains the complexities of epilepsy treatment, the challenges of drug-resistance, and where he thinks that we should take things going forward - if we really want to improve people's quality of life. Hear how learning more about brain mechanisms and causes of causes could lead to improved understandings and treatments. Watch/listen/read here 👇!
Episode Highlights
Why 1 in 3 drugs fail
The leading theories behind drug resistance
Why genetics isn't the whole answer
Where future epilepsy treatments may come from
About Graeme
Graeme Sills is Senior Lecturer in Pharmacology at the University of Glasgow, where he is Year 3 lead and Deputy Director of the BSc (Hons) in Pharmacology degree programme, and holds fellowships from Advance HE and the British Pharmacological Society. He sits on council of the ILAE (British Branch), the steering committee of the UK Epilepsy & Pregnancy Register, the Education & Training committee and Meetings committee of the British Pharmacological Society, the editorial board of five scientific journals, and is Honorary Vice-President of the Epilepsy Research Institute UK.
Full profile: Grame-Sills
Topics mentioned
drug-resistant epilepsy
drug transporters
blood-brain barrier
neural networks
genetics
pharmacogenetics
future research
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Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds
Pharmacological Reviews, 1990 Sep
Rogawski MA, Porter RJ.
42(3):223-86.
PMID: 2217531
DOI: https://doi.org/10.1016/S0031-6997(25)00046-8Identification of Refractory Epilepsy
N Engl J Med, 2000 Feb
Kwan P, Brodie MJ. Early
3;342(5):314-9.
PMID: 10660394
DOI: 10.1056/NEJM200002033420503Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina.
Neurology, 2001 Jul
Sills GJ, Patsalos PN, Butler E, Forrest G, Ratnaraj N, Brodie MJ.
24;57(2):196-200.
DOI: https://doi.org/10.1212/WNL.57.2.19Lack of association between the C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment.
Epilepsia. 2005 May
Sills GJ, Mohanraj R, Butler E, McCrindle S, Collier L, Wilson EA, Brodie MJ.
46(5):643-7.
DOI: https://doi.org/10.1111/j.1528-1167.2005.46304.xDrug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options
Pharmacological Reviews, 2020 Jul
Löscher W, Potschka H, Sisodiya SM, Vezzani A.
72(3):606-638.
DOI: https://doi.org/10.1124/pr.120.019539 -
Trailer
00:00 Grame Sills
“Some people, have a set of genetic factors that individually don't have a significant influence but collectively if you bring these factors together in one person means that they are less likely to respond to their medicine.”
Intro
00:16 Torie Robinson
About 30-35 years ago, we had 30% off people with epilepsy whose seizures couldn’t be controlled by medication. Now, today, 2026, the percentage is basically the same? And that’s despite huge developments in medicine, pharmacology, technology - things just haven’t changed for those millions of people! I’m Torie Robinson, this is Epilepsy Sparks Insights - and let’s try and get some answers from today’s fabulous guest, Dr. Graeme Sills.
Meet Graeme Sills
00:45 Torie Robinson
Hi there Graeme, thank you for joining us today. Could you tell us just a bit about yourself and what you do please?
00:50 Graeme Sills
Hi Torie, well thank you first of all for inviting me to take part. I'm Graeme Sills, I'm a pharmacologist, which means I'm a scientist who's interested in how drugs work. I'm currently a senior lecturer in pharmacology at the University of Glasgow where I lead the third year of a 4 year degree programme in pharmacology and I spend most of my time teaching pharmacology to undergraduate students. Prior to that I spent several, 3 decades and more, in academic positions here in Glasgow and at University of Liverpool where my main focus was actually in epilepsy research and epilepsy therapeutics.
Introduction to pharmacology and epilepsy
01:29 Torie Robinson
How is epilepsy to do with pharmacology? I mean, lots of our listeners will be like “Dude, it's obvious!”, but just give us the lowdown.
01:36 Graeme Sills
The principal treatment for the vast majority of people with epilepsy is medication or drugs and it has been for well over a hundred years since the first anti seizure drugs really were introduced. And, with the exception of some people who are candidates for epilepsy surgery perhaps, or maybe have a vagal nerve stimulation the vast majority of people take antiseizure medications, sometimes more than 1 and sometimes several.
02:08 Torie Robinson
Yeah, it's delightful, right? Well, despite the delightfulness of taking the medications anyway… Oh look, for some people, they're fine. For lots of people, they're fine. And that's great, isn't it?
02:17 Graeme Sills
Yeah.
Challenges in epilepsy treatment
02:17 Torie Robinson
We always hear the worst of the worst. But for those worst of the worst, 30% of people with epilepsy don't have been controlled by the drugs that we have. And that seems to have not changed over the past 20 years, despite developments. So what's that about?
02:31 Graeme Sills
Yeah, it's really interesting because there's been a lot of activity in terms of development of new antiseizure medications. In my research time (I started epilepsy research in 1990) we were just starting to see drugs like Lamotrigine come onto the market and so it was a really exciting time in epilepsy therapeutics because we thought all of these new drugs were really going to change the picture. And here we are 35 years later… and you're absolutely right. The proportion of people who have good control of their seizures with antiseizure medication hasn't really changed that much. The profile of the drugs has perhaps changed a little bit, maybe, you know, their side effects are a bit more tolerable. There are always new drugs who come along that for any given patient that drug is fantastic, but if we take people with epilepsy as a whole, those 20, 25 new drugs that we've seen over last 3 decades haven't made a significant difference and that's really frustrating for those of us involved in research into antiseizure drugs and undoubtedly far much more frustrating for people with uncontrolled epilepsy.
03:46 Torie Robinson
And also, I think for carers as well, because sometimes we have lots of people who can't look after themselves overly well. That's like the whole of epilepsy. It the ripples out really, isn’t it. It’s the impact of these things. What are the explanations for this, though? So we've got this massive issue. Do you know why 30% of us?
04:04 Graeme Sills
Oh, I wish I did, Torie! It's something I've been really interested in since, kind of, the late 1990s, early 2000s, when we really started to think about what is drug-resistant epilepsy and what is the explanation why 2 people with seemingl developed......ways to protect itself so that it's not exposed to chemicals or toxins or poisons thay similar conditions can respond completely differently to medication? And some people will achieve very, very good seizure control with the first or maybe second drug that they ever are exposed to. And yet someone else, who on the surface, looks like they've got a very similar condition, doesn't respond at all no matter what drug you use or what combinations of drug you use. So, there was a lot of research that really kicked off around that time trying to understand the underlying biology of drug resistance in epilepsy. And it focused on a variety of different things. We were thinking about “Do the drugs get into the brain in people with drug resistant epilepsy? If they do get into the brain, what effects are they having in the brain? Is the brain different in people with drug resistant epilepsy (compared to those who are well controlled) and what other factors might be responsible for that?”. It's interesting (just as a little side point) but actually if you look at other common CNS conditions things like schizophrenia or cognitive mood disorders like bipolar disorder and things like that it's roughly about the same proportion of people in each of those conditions who don't respond to medication. It's often about one third of the population. And that led us down the track of thinking “Maybe there are common mechanisms in the brains of individuals that make them either drug-resistant or drug-responsive and it doesn't really matter what CNS condition they have?”.
05:54 Torie Robinson
64)Well, and isn't that also interesting because you're much more likely to have an epilepsy if you have schizophrenia, right? And vice versa. For instance, it's like, what is that initial muck up that may cause both sort of symptoms or diseases?
06:08 Graeme Sills
Yes, that was one kind of initial focus: maybe there are common mechanisms that just determine almost from birth whether you're a responder or a non-responder. But I think we've kind of dismissed that idea now. But it was just because there were similar proportions in different disease areas.
06:26 Torie Robinson
So what are you thinking now after 30-35 years?
Why the drugs don’t work: the drug-transporter hypothesis
06:30 Graeme Sills
I mean there have been a number of publications in this field even right up to some recent review articles that have looked at this and there are about 6 or 7 theories that have been postulated over the years about why some people respond to their medication and others don't. One of them is around brain penetration of drugs and there are special proteins that are expressed in the blood vessels that supply blood to the brain that are designed to keep chemicals out of the brain. And this became known as the drug transporter hypothesis and was probably the kind of most... the favourite one in the early 2000s, people thought that maybe we've got something that stops drugs getting into the brain and that's more prominent in some people than others.
07:20 Torie Robinson
The blood-brain barrier?
07:21 Graeme Sills
Yes, so the blood-brain barrier is an interesting thing. So obviously all of the tissues of our bodies are supplied by blood via the blood vessels, the arteries and the arterioles and the capillaries. And in some parts of the body, the blood, the chemicals in the blood can move quite freely from the blood into the tissue and back into the blood and they're kind of leaky, if you like…
07:45 Torie Robinson
Mm-hmm.
07:45 Graeme SillS
…but the brain is not one of these places... the brain has, from an evolutionary perspective, has developed ways to protect itself so that it's not exposed to chemicals or toxins or poisons that we might inadvertently consume. And so it has what we call the blood-brain barrier which is a series of biological processes that are designed to keep chemicals out of the brain in order to protect the brain from any potential harm. And so, the theory was that in people with drug resistant epilepsy, their blood brain barrier had somehow become strengthened and that it was extra good at keeping drugs out of the brain and that was, by and large, by over-expressing these drug transporters which are designed to keep chemicals out of the nervous system.
Why the drugs don’t work: the network hypothesis
08:38 Torie Robinson
And what else? What's another reason?
08:40 Graeme Sills
Oh, so there's… there are a number of things. I think the one that I probably put the greatest amount of faith in is the network hypothesis where in people with epilepsy, the brain kind of rewires itself a little bit. And we know that every seizure can cause changes in the brain, which means that neurons (which are the key), the key cells in the brain that communicate with one another can start to communicate inappropriately with other cells in the vicinity, and that over time when people experience a number of seizures we get we build up this kind of rewired network of connections in the brain which means that that brain is somehow different from what we would see in normal circumstances and someone who has perhaps very infrequent seizures or someone who doesn't have seizures at all.
Why the drugs don’t work: the severity and genetic hypothesis
09:31 Graeme Sills
So there's the network hypothesis there's the intrinsic severity hypothesis which in simplistic terms means the worst the epilepsy, the harder it is to control. There's the genetic hypothesis which suggests that we're all genetically different and that we, some people, have a set of genetic factors that individually don't have a significant influence but collectively if you bring these factors together in one person means that they are less likely to respond to their medicine.
Future directions in epilepsy research
10:06 Torie Robinson
Pretty complex stuff. And so, with these hypotheses (being plural), what are the next steps or current steps being looked at in pharma?
10:16 Graeme Sills
Yeah, so I think there's still some interest in the drug transporter hypothesis and the brain penetration of drugs. Although, I think that has been debunked to some extent through about 2 decades of research, I think there's still some interest in how we might improve the penetration of drugs into the brain in order to optimise their efficacy but hopefully not compromise or make the side effects worse.
10:42 Torie Robinson
Tell us a bit about that. How would one do that, potentially?
10:45 Graeme Sills
Well, there are drugs that are still experimental. They're not used clinically for any particular condition, but we use them in a laboratory setting in models, in cell cultures, in experimental models of epilepsy, where we can manipulate these transporters and we can block their effects, and we can look to see how that improves antiseizure drug penetration across the blood brain barrier, for example. So, there was some interest in that... as I say, that’s kind of died out a little bit and the epilepsy world has moved on and I think there's been a lot of interest also in genetics and there's there are massive efforts to understand the genetic basis of epilepsy itself and how genetics contributes to the development of the condition but attached to that there have also been a series of studies that have looked at genetic variability between individuals and how that affects their response to epilepsy medication. So, what we would call pharmacogenetics or pharmacogenomics as opposed to just genetics.
Torie Robinson
I find this fascinating. Personally, we did an interview with a fabulous, fabulous scientist talking about how you can have identical twins, both with the same genetic abnormality causing the epilepsy, but the symptoms are so noticeably different, the severity of everything. And you would think, like, for the uneducated, give them the same treatment, it'll work the same, but no!
12:18 Graeme Sills
And I think this really reflects our still limited understanding of what is going on in the brain of people with epilepsy. And the reality is that it's almost an individual disorder in people. We can't say for certain that 2 people will have the same underlying biological cause of their epilepsy. And even in identical twins where we have, they're genetically identical, but they have different features of their epilepsy and they respond differently to medication, it’s because there are other factors involved and they might be environmental, might be biological, they could be psychological, we genuinely don't really understand what all of the various influences on underlying day-to-day brain function are and that's one of the real challenges I think.
Innovative approaches to research and treatment?
13:08 Torie Robinson
To say the least. Is there something we're not looking at that we should be looking at? So should we be looking at genetics further? Do you think that we should be looking at prevention rather than treatment? Where do you stand on that?
13:21 Graeme Sills
I think there's a number of things. And I have to say, I'm not an expert in there… there are far more experts in these things than I am. Far cleverer people than I am are involved in this kind of thing! From my somewhat simplistic pharmacological perspective, I think there are a few things we can do. I think we can do better genetic studies. But that comes with a challenge of globally working together and using the same criteria to characterise the epilepsy and characterise the response to treatment in the epilepsy so that we can generate studies of sufficient size that allow us to detect relevant signals. One of the challenges I think, and it’s certainly in the pharmacogenomic side of things in epilepsy so far, has been the noise that's in our experimental approaches. We have people with quite disparate types of epilepsy in the same study. We are looking at responses to drug treatment, but we're just kind of considering all drugs as equal and not looking at very specific drugs in very specific types of epilepsy. And that's largely because the studies aren't big enough to allow us to do that. So, from a genetic perspective we can do cleaner and better designed studies but those are massively challenging in terms of getting the individuals into that. And exactly, the cost of those is phenomenal and getting everyone to do exactly the same thing in every single epilepsy research site around the world is also difficult. So genetics has still got somewhere to go. But I, you know I come back to the identical twins thing; it's not going to be the whole answer to the question! So there are other things to do as well. I do think in terms of treatment, we need to start to think a little bit more outside the box. We… despite the fact that we've had 25 new drugs since the early 90s, they are all a little bit the same, if you like, in terms of how they work.
15:29 Torie Robinson
Mm-hmm.
15:29 Graeme Sills
They all kind of do the same things in terms of the way that they interfere with neural function and communication between nerve cells. And so I think we need to get off that track of developing drugs that are kind of just the same as the last drug that came along and start to think about other biological processes like inflammation that occurs in the brain, the involvement of the immune system (if we believe that's important in some types of epilepsy). We need to think about what's going on inside nerve cells and not just on the surface of nerve cells because that's really what we've targeted pretty much so far. So the pharmacologist - and I have to hold my hand up here, we need to start advocating for a kind of more… a broader range of pharmacology and epilepsy and not sticking to traditional things that we've looked at previously.
16:21 Torie Robinson
I couldn't agree more. It's kind of thinking, I hate these terms, but like "outside the box".
16:26 Graeme Sills
Yeah.
16:26 Torie Robinson
Isn't it, right? It kind of is!
16:28 Graeme Sills
"Blue sky" thinking, that kind of… yeah! But it's true! It's true, we have to be more innovative. But in order to be innovative, we also have to have the under… we have to know what causes epilepsy in order to know where to direct our efforts. And that's probably where we really need to start: is understanding the causes so that we can then start to develop the treatments, whether they're drugs or something clever, like gene therapies that will genuinely target that underlying cause. And that's what we've not done successfully so far.
17:00 Torie Robinson
It's kind of hard to get outside of this box which we've been contained in for decades and not looking beyond. Sometimes I think we'll be saying “Okay, this is the cause.” but actually sometimes we need to say “Well, what's the cause of that cause?”? It's not as simple as just one thing causing the other. It can be many, different things interacting.
17:21 Graeme Sills
Yeah, I... people have probably said this numerous times over many decades, but I do think we're kind of on the cusp of having the tools now to go that extra step. The advances in technology around scientific investigation, in brain imaging… and all of these things collectively can help us understand what causes the epilepsy. So there's still opportunity that we should still be positive about where we can go next because I think we have the tools at our fingertips to really start to understand the condition a lot better.
Closing thoughts and thanks
17:58 Torie Robinson
Thank you to Graeme for sharing his wisdom, experience of over 30 years as a pharmacologist, and indeed for reassuring us that despite the rather apparent, limited progressions in helping people with refractory epilepsy - that there is real hope for the future. Subscribe to support our channel - if you haven’t already - and see you next time!