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Schizophrenia Forum Radio

Schizophrenia Forum Radio is the official podcast of the Schizophrenia Research Forum website, an independent news and discussion source on current science of schizophrenia and related research.
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Mar 29, 2016

Schizophrenia Forum Radio: Episode 5, featuring an interview with Kristen Brennand describing the potential of stem cells to help us understand the elusive pathology of psychiatric disease.

 

[intro music]

 

Hello, and welcome to the March 2016 podcast of the Schizophrenia Research Forum. I’m your host, Kate Lohman.

 

Schizophrenia Research Forum was originally funded by the U.S. National Institute of Mental Health, and is now a project of the Brain and Behavior Research Foundation, the major private funder of research into mental and emotional disorders. All of our content is entirely open to the public.

 

This episode features an interview with Kristen Brennand, discussing the logic for using stem cells generated from skin cells from people schizophrenia and other complex disorders. How can this help us find better treatments?

 

But first, here is a summary of some of the latest features you will find online at Schizophrenia Forum dot org.

 

First, we have a mixture of sad news and accomplishments. As 2015 ended, we celebrated our tenth year providing news, discussion, and resources about the search for better treatments for psychotic disorders. But not long into the new year, Connie Lieber passed way. Connie helped make the Forum a reality by putting the support of BBRF behind us more than ten years ago. Coming shortly after the death of Ted Stanley, it was a tremendous blow to the mental illness research community. You will find articles about these highs and lows from December and January in the news section of our website.

 

On the research front, the biggest news in awhile is the first lead from the big genome-wide association study of 2014. The risk genes for schizophrenia that lie hidden in the genetic swamp of the MHC region of chromosome 6 have eluded researchers since the days of linkage studies. But Steve McCarroll at Harvard University and the Broad ["Brode"] Institute has fished out a likely culprit: a version of the immune system molecule "complement component 4." His collaborator, Beth Stevens of Boston Children's Hospital, then linked C4 to cortical thinning in schizophrenia during development. The study thus connects three seemingly separate observations about schizophrenia: It typically emerges in adolescence or young adulthood; it is associated with cortical thinning and synapse loss; and it has been associated with immune system genes. The story can be found in our news section, published on January 28.

 

We also point you to the survey article, "Early Psychosis Research Matures, Going Both Deep and Wide," by Michele Solis, published February 15. Rather than focus on one or several studies, Solis interviewed some of the leading researchers who study people who are going through what we hesitate to call mild symptoms of psychosis. These scientists describe what they see as the most promising paths to understanding how these young people will progress: Will they develop schizophrenia or will they develop other mental illnesses, or will they go on to a life free of psychiatric diagnoses.

 

Finally, there are a couple of studies in recent months that provide clues to how lithium helps to reduce bipolar disorder symptoms, and how to determine who will benefit from lithium. In a story posted November 3, we reported on a paper in Nature by Rusty Gage of the Salk Institute and colleagues that used pluripotent stem cells created from the skin cells of patients. The researchers determined that neurons created from the stem cells of patients had different excitability characteristics from those of control subjects. This could both provide clues to how bipolar disorder affects brain circuits and offer a way to test whether people with bipolar disorder will respond to lithium.

 

On the same theme, our February 15 news story covered a study led by SRF advisor Francis McMahon of the US National Institute of Mental Health, among others, published in the Lancet. The researchers found that a genetic signal on chromosome 21 could help determine how people will respond to lithium. The results from this genetic marker may only apply to a very small number of people with bipolar disorder, but they support the idea that determining people's genotypes can help guide medication choices.

 

[transition music]

 

Now to the interview.

 

Schizophrenia Forum Editor Hakon Heimer talked with Kristen Brennand of Mount Sinai School of Medicine at a recent Banbury meetings at Cold Spring Harbor Laboratory. Working in Rusty Gage's lab, Brennand was the lead researcher on the first major paper using induced pluripotent stem cells from people with schizophrenia, described in a news story published on SRF April 13, 2011.

 

 

Interviewer – Hakon Heimer

How, in theory, can creating stem cells in people with schizophrenia or any other disorder help us understand or even better treat these disorders? What's the best case hope?

 

Interviewee – Kristen Brennand

So for most human diseases, there's a lack of live human cells for study. With the obvious exceptions of diseases like obesity or cancer, we really, as scientists, can't study the human material, and this is particularly true for schizophrenia. We can't get access to live human brain tissue from patients, and we certainly can't get access to live human brain tissue from controls. And so I think this has really limited the field so far. We've been able to do studies of blood for genetics or of mice to recapitulate aspects of disease, but we've never been able to ask specifically what type of human neurons have aberrant activity in schizophrenia, and then to go in and dissect what genes and what proteins are misfunctioning to cause those abnormal activities. And so, with stem cells, for the first time, we have the ability to generate any cell type affected in any disease with a genetic background completely identical to that of the patient.

 

And so what stem cells allow us to do is to generate neurons, astrocytes, oligodendrocytes that are genetically identical to patients, compare those to controls, and ask a couple of really simple questions. They let us ask: what cell type is primarily affected in schizophrenia? How is that cell type affected? So, for example, are neurons larger or smaller, better connected/worse connected, firing more/firing less? And then to ultimately ask why are they different, and how can we make the same again?

 

Interviewer – Hakon Heimer

Do you need to be able to create networks or neurons, and is that a hope for the future?

 

Interviewee – Kristen Brennand

We definitely want to get there. Absolutely the field will need to be able to make networks. But I think there are some questions to ask along the way. And what I mean by that is if you ask anyone in the field what neuronal cell type is most affected in schizophrenia, what you start is an argument about glutamatergic, GABAergic, and dopaminergic neurons. We're not even sure at this point how much of a role cells like astrocytes and oligodendrocytes have. So I think the first thing we need to do is make pure populations of each of these candidate cell types – the major players that we think might be involved – and ask at the cell-autonomous level: Which of these cell types on their own have defects in schizophrenia? And then once we've asked it on the pure cell types, I think then we're ready to begin building networks and ask how these things grow organically out of the networks.

 

Interviewer – Hakon Heimer

So, what would you say are the limitations of the field?

 

Interviewee – Kristen Brennand

So this field is particularly young. What we do was impossible when I started graduate school. It was first shown in 2006 that you could turn skin cells into stem cells—in fact, the discovery in 2006 for which the 2012 Nobel Prize was awarded. And so, this field is less than 10 years old, and there's a lot of things we're still figuring out. We're not that great at making neurons yet. And what I mean by that is we make neurons about as slowly as Mother Nature. So, if I spend three months in the lab making neurons, they look a lot like first-trimester fetal brain tissue. And, of course, schizophrenia is a disease of adults, not fetuses. So we're still really modeling predisposition.

 

So one of our major problems is how young the neurons are. And there are lots of people – not just in the schizophrenia field but in all the neurological fields – working together, all the iPS researchers are all in this together trying to find faster and better ways to mature neurons. Another problem that we have is that the cells that we make are still a bit heterogenous, so we have mixtures of cells. We're getting better at making some types of pure cells, but we're still not absolutely perfect at making exactly the cell type that we want. And because we're not perfect at making the cell type, the connections they form with their neighbors are sometimes not the same ones they would form in the brain. Neurons synapse to the next closest cell perhaps and not the one that physiologically they ought to be connected to.

 

And finally, I think our last problem is that these cells aren't myelinated still. We cannot get human oligodendrocytes to myelinate human neurons in vitro. And we know this is really important in the brain. Along those lines, we can make some types of astrocytes but not all, and we're really not making good microglia yet. So we're not at the level of capturing all the complexity of the brain.

 

Interviewer – Hakon Heimer

Which of these challenges would you say you're the most optimistic about finding solutions for in the next few years?

 

Interviewee – Kristen Brennand

I actually think they're all tackleable. So if the problem is making more defined cell types, I think the strength of that is that many scientists in many fields benefit from that. So whether they're studying Parkinson's or Alzheimer's or schizophrenia, everybody wants microglia. And when a lot of scientists have a common goal, I think that gets tackled. So the cell types I do believe the field will take care of. The next question is scalability, and I think this is a major issue in the field and one that's going to be the hardest to address. Right now all the iPS cell studies study four patients, 10 patients maybe, but the geneticists have already told us that if you're not looking at 10,000 people you're missing a lot of the complexity of disease. And so, this might be an engineering problem, this might be a robotic problem; it's certainly a money problem. And I think it's going to take us, as a field, five or 10 years to even really know how to address this. But the geneticists took just as long to figure it out, and I do think it's solvable. I think there's evidence that consortiums of scientists have solved big problems like this in the past. But this is a big problem that no single scientist will be able to solve.

 

Interviewer – Hakon Heimer

Are there any developments in related fields – in genetics or, for example, growing organoids in a dish – that you're really excited about and applying to your work, and that you think would dovetail nicely with your work?

 

Interviewee – Kristen Brennand

So I think one of the best things about working with stem cells is that you get to adapt the best advances from every field. What the geneticists are doing is getting much better at understanding at the level of a single patient whether there are defined penetrant mutations involved in that person's disease. And so those are testable hypothesis that we can now go in and look at that mutation. If I fix it, how do the cells get better? Could I make control cells get worse if I added just that one mutation? Do I have to add two mutations or three? And we can look at the additive effects and penetrance of all the best loci identified by the geneticists.

 

The neurobiologists are getting better at looking at synapses and looking at neuronal function and developing assays that we get to keep using as stem cell biologists. Optogenetics is another discovery that was impossible five years ago, and now with light, neurobiologists can make neurons fire. So now I can imagine an experiment where I have a mixed population of defined glutamatergic and GABAergic neurons in a dish, and I make all of the glutamatergic neurons fire, and I record from all the GABAergic ones. And we can do this with mixed populations of control glutamatergic and patient GABAergic or vice versa. And so, the ability to adapt these techniques, these hypotheses from the geneticists, these techniques from the neurobiologists, and yes, the stem cell biologists, too, where we're getting better at making more cell types, at making them in 3D. And I think every advance that the stem cell scientists make get us closer to relevance of the human brain. It's a more accurate model every time we add complexity. And I think together – with the stem cell biologists, the neurobiologists, and the geneticists – we can ask better questions more precisely and get more meaningful answers.

 

Interviewer – Hakon Heimer

There have been a handful of papers – besides your paper from a few years ago – and do you feel that any of those have really told us something about schizophrenia yet, or is that still something to wait for?

 

Interviewee – Kristen Brennand

So I know of already six or seven iPS papers from groups as far away as Israel and Brazil and across the US. And I think in aggregate these studies show us a few things. One, despite the fact that this is an adult-onset disease with cells that we're studying using cells that are most likely fetal, we are able to capture predisposition. So as a field, all these groups are seeing phenotypes, and most remarkably on different cohorts of patients with different genetic lesions collected in different countries around the planet we're seeing commonalities. So, many groups have now shown things like reduced synapse density, reduced synaptic activity, and increased oxidative stress. So, I think that what we're showing is that it's possible. And every time more groups show that with a, you know, a few more patients here or there I think we help bring in the next generation of scientists to help cover more patients and ask better and deeper questions.

 

Interviewer – Hakon Heimer

Thanks a lot.

 

Interviewee – Kristen Brennand

It's my pleasure. Thank you.

 

[transition music]

 

Thank you for listening to this podcast from the Schizophrenia Research Forum. If you enjoyed the podcast and find Schizophrenia Research Forum helpful, please consider supporting us with a donation. We are a small team of freelance editors who strive to provide a well-informed, independent view of the research that could help the millions of people across the globe who suffer from schizophrenia and other psychotic disorders. Help keep us going by visiting our website and clicking on "Support Us" link in our table of contents on the left side of the screen.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to Editor Hakon Heimer at info@schizophreniaforum.org.

 

[outro music]

 

Sep 23, 2015

Schizophrenia Forum Radio: Episode 4, featuring an interview with Robin Murray discussing recent research on the relationship between cannabis and psychosis.

 

[intro music]

 

Hello, and welcome to the September 2015 podcast of the Schizophrenia Research Forum. I’m your host, Kate Lohman.

 

Schizophrenia Research Forum is in its 10th year of providing news, discussion, and resources about the search for better treatments for psychotic disorders. We were originally funded by the National Institute of Mental Health, and are now a project of the Brain and Behavior Research Foundation, the major private funder of research into mental and emotional disorders. All of our content is entirely open to the public.

 

This week’s podcast features an interview with Robin Murray of the Institute of Psychiatry, Psychology and Neuroscience at King's College London on the latest installment in his group's research on the relationship between cannabis and psychotic disorders.

 

But first, here is a summary of some of the latest features you will find online at Schizophrenia Forum dot org.

 

First, we point you to our survey of schizophrenia genetics. Reporter Michele Solis spent many hours interviewing leaders in psychiatric genetics on topics ranging from the different gene-finding strategies to how we might follow up on the leads they have generated. The five articles can be found in our News section, published between August 7 and August 25.

 

In a July 15 news story, we report on two studies that attempt to address the question of whether current brain imaging technologies can show brain changes over the course of schizophrenia. The authors of one study suggest that there may be a subgroup of patients who experience progressive loss of tissue in the cerebral cortex. The second study, conducted on a rare group of never-medicated patients in China, does find differences in the brains of people with schizophrenia, though they cannot be certain when the changes happened.

 

Another study, which we reported on August 11, finds that a long-acting injectable version of the antipsychotic drug risperidone is six times more effective than the pill version for preventing relapses of psychotic symptoms among people in the earliest stages of schizophrenia. Several commentators make the argument that long-acting injectibles should not be reserved only for people who have had the disease for years and are unable to stay on the medications.

 

Also worthy of mention is the relaunch of our What We Know About Schizophrenia table. It has been given a facelift to make it easier to read, and we have updated the genetics section.

 

Finally, if you want to organize a symposium at the Schizophrenia International Research Society meeting next spring in Florence, October 1 is the time to get your proposal in. You'll find a box on our homepage with information and links for the meeting.

 

[transition music]

 

Now to the interview.

 

Schizophrenia Forum Editor Hakon Heimer talked with Robin Murray at the International Congress on Schizophrenia Research in Colorado Springs, and Murray laid our his argument for why he is convinced that cannabis plays a causal role in the development of schizophrenia. The recent context for the interview was an article in Lancet Psychiatry by Marta Di Forti, Murray and their colleagues, in which they report that people who smoked cannabis with greater amounts of THC were more more likely to have psychotic disorders.

 

Interviewer – Hakon Heimer

Since we're here in Colorado, one of the experiments in legalization of marijuana, it seems appropriate to talk about your new report in Lancet Psychiatry on the correlation between cannabis use and psychosis. First question, how is the design of this study different from earlier work in the area?

 

Interviewee – Robin Murray

First of all, I should say of course, the lead author is not me but Marta Di Forti, and this is a study that assumes causality; we've done lots of work and I certainly believe that heavy use of cannabis – marijuana – does increase the risk of schizophrenia. So what we were looking at is all people who came into the services in South London over a period from 2005 to 2011 with psychosis, and we took a detailed history of cannabis use, and then we studied about 400 controls. So we had just over 400 cases and just under 400 controls where we had similar information on how much cannabis they've taken, how long they've been using, what type of cannabis, a bit like the sort of history you would take from someone about their alcohol intake. Usually in cannabis studies, people just say do you use cannabis, yes or no, and that's it. But really to understand the role of cannabis, you have to take a detailed history as if you were taking an alcohol history.

 

Interviewer – Hakon Heimer

And what were your results, and do they support or change the way to interpret earlier work?

 

Interviewee – Robin Murray

Well, first of all, they show that your risk depends on what type of cannabis (we say cannabis, I think in the states you say marijuana) what type of cannabis you're using. So in Britain, there are essentially two types; there is traditional cannabis which was taken as cannabis resin, or hashish, and that contains about 4% THC and 4% of an ameliorating compound called CBD, whereas there is a more potent, more modern version which is sensimilla, or skunk, which contains about, say, 18% - 16 to 18% - of THC and no CBD.

 

And what we found was that we did not find any increase in the risk associated with the use of old-fashioned resin, or hash, but we found that the use of the more modern skunk, a sensimilla cannabis, that this increased your risk proportional to how often you used it. So if you used it, say, once or twice a month, that would double your risk of developing psychosis, if you used it, say, every weekend, that would increase it to about three times, and if you used a skunk sensimilla cannabis every day, your risk went up fivefold. So this is consonant with a lot of other evidence that it's the concentration of THC in the cannabis that matters, and also that counterbalancing effect of the CBD. So the least psychotogenic type of cannabis is low THC with high CBD, and the worst type is high THC and no CBD.

 

Interviewer – Hakon Heimer

So this addresses in some ways the earlier research that showed that there was some beneficial effects of marijuana, and then some of that has led to drug development efforts, I understand, for compounds based on marijuana that would be used to treat psychosis. Is that true?

 

Interviewee – Robin Murray

Yes. So the cannabis plant produces 70 or 80 different compounds, but the big two are THC – tetrahydrocannabinol; THC has the psychotogenic effect and also the high, why people take it – and CBD produces a more anxiolytic type of effect. And so there is one study which had suggested that CBD may have antipsychotic effects. There are now replications attempted, so we don't really know whether this is true or not.

 

But what we do know is we have done studies where we give people THC – your listeners have met professors before, when we say "we" we mean somebody else – so a PhD student or a post-doc gave THC to normal volunteers, you make them suspicious, hostile, a bit paranoid for a few hours. But if you give them CBD first, you don't get that effect; you get a very small increase in the psychosis score. You don't seem to interfere with the euphoria, but you do interfere with the psychotogenic effect of the THC, and also the cognitive impairment. So if CBD can ameliorate some of the effects of THC, and if there's one study looking at it as a possible antipsychotic, then naturally we begin to think of other uses for it.

 

So in Europe, there is one study funded by the EU – the European Union – across several countries looking at CBD as an add-on therapy, but then another question is could you use CBD for people in the prodrome? You don't want to give people in the prodrome heavy-duty antipsychotics because of all the side effects. CBD doesn't have bad side effects, and therefore it might be a possible benefit to people in the prodrome. And, of course, here in Colorado CBD is being used a lot for childhood epilepsy; people are moving to Colorado if they have a child with intractable epilepsy because they can get ahold of CBD.

 

Interviewer – Hakon Heimer

So back to your most recent results. So what are the policy or science or clinical implications of what you found out about high THC cannabis?

 

Interviewee – Robin Murray

Well, I've told you half the results. The other half and the part that got headlines was that we calculated the population-attributable fraction, and so that is the proportion of people with their first episode of psychosis who would not have broken down, gone psychotic, if they had not used high-potency cannabis, and that came out as 24%. Now there have been other studies in the past; a study in New Zealand suggesting 8%, a study in Germany suggesting 12%, Holland 15%. This is the highest reported proportion of psychosis attributed to cannabis, and I think that is because, curiously, the English smoke more cannabis than the Dutch. And in Europe, we always think the Dutch have the permissive attitudes, but at South London we smoke more cannabis and we smoke a lot of the high-potency cannabis. So I think this is why we have found a higher proportion of psychosis can be attributed to a high-potency cannabis than in other countries.

 

So this doesn't mean that for one-quarter of all people with psychosis, the only causal factor is cannabis; it may be that some have a genetic predisposition. Well, we know that that's a fact; it may be that some have been abused as children or had horrendous events of the type that we know can increase risk of psychosis, but they wouldn't have been tipped over the edge into psychosis had they not used high-potency cannabis. So psychosis is a big problem, as you and the listeners know; if we could get rid of 24% of psychosis in London and maybe not quite such high proportion, but 15%, 20% elsewhere, this would be a big deal.

 

Interviewer – Hakon Heimer

So do you favor more preventive measures, rolling back legalization as a way to do this? How do we prevent that 24%, given that prohibition of alcohol was such a problem, and prohibition of cannabis hasn't really reduced the availability of cannabis?

 

Interviewee – Robin Murray

I'm not a great believer in legal constraints having a big effect. In Britain, something rather odd happened; we made cannabis slightly less illegal in the early 2000s as a response to newspaper pressure. Once the government had done that, the newspapers changed their mind and attacked them for being too liberal, so they then after four years, they changed it back again. Neither of these things had any effect on consumption of cannabis, except that each time there was a debate about it, it gave us the opportunity to educate people; to get on the television and say to predominantly young people it's not an entirely safe drug. It's like alcohol, if you use it sensibly and moderately, you'll probably come to no harm, but if you drink a bottle of vodka a day or you take five joints of high-potency skunk a day, then you are running the risk of developing a psychosis.

 

And an interesting thing has happened in Britain and elsewhere in Northern Europe, in that cannabis consumption has fallen considerably. In Britain, it's fallen by 20% in young people over the last 10 years. Whether that's to do with education—it may be partly to do with education—and it may also be partly to do to the fact that more young people have seen one of their friends have a brief psychosis following high-potency cannabis. So I think we should educate people.

 

And, of course, there are experiments going on; there are studies in animals and there are studies in Americans. And so there is a big experimental study going on here in Colorado, and I think in Washington, and in Uruguay, of course, so why not wait and see what happens. Maybe it'll be a great success, maybe the legalization will enable people to know exactly what they're buying, and perhaps they would buy less of the high-potency cannabis and more of the old-fashioned cannabis. I think for those of us in other countries, it's worth just waiting to see what happens.

 

Interviewer – Hakon Heimer

Could you address the alternative explanations and how you would determine their contribution, that is, either a reverse effect – self-medication – or a common etiology where hypothetical genetic or environmental risk factors could independently increase both the likelihood of using drugs and developing psychosis?

 

Interviewee – Robin Murray

So we do know unquestionably that cannabis use is associated with a later increased risk of psychosis; there are now nine prospective studies that have shown that. It's a modest but a consistent effect and it's a dose response. But as you correctly say, it could be that there might be other explanations. Now it was suggested that perhaps people who were taking cannabis were also taking amphetamine and other drugs. That has been excluded. It was suggested that perhaps the people who were using cannabis were odd or peculiar. Now in my area, 66% of Londoners have used cannabis—now they're not all peculiar; some of them may be—but I think the evidence that cannabis users are odd is very weak.

 

You might say, Are people who are heavy cannabis users in some way different? For example, in the Dunedin study which we were involved in, we took all of those who appeared to have minor psychotic symptoms at age 11 and chucked them out, and so we just were left with the healthy teenagers. And if they started using by 15, in the whole population the odds ratio was 4.5; if you chucked out the ones who are a bit odd, the odds ratio fell to 3. So there's no doubt that people who are a bit paranoid or suspicious or they have a family history, there's a greater risk. But the evidence we have is that people who show no other evidence of peculiarity, if they use cannabis very heavily they were prone to go psychotic.

 

And one of the interesting things from the clinical studies is that people who develop psychosis following the use of cannabis, and indeed other drugs, were often cleverer and more sociable than other people who developed schizophrenia. So as you know, a proportion of people who develop schizophrenia have a neurodevelopmental problem that, say, results in them being a bit slow to meet their developmental milestones; they maybe have temper tantrums, they don't get on so well with peers, they're not as good at school as their brothers and sisters, so there's that developmental group. Now the people who develop psychosis following use of drugs are not at all like that. They are smart, they are sociable, they're good at sports; in fact, one of their troubles is they're a bit street-smart, because they've got so many buddies that they can go with their buddies find the dealer when they're 11 or 12, and they're also clever enough to get the money out of their parents to keep the habit going without their parents knowing. So there are differences clinically between these two groups.

 

The big question has been what about the question of a polygenic risk score, and is there a correlation between having a high polygenic risk score and being a cannabis user? There is one large twin study which came from our institute, by Rob Power, and he looked at twins in Australia and showed that a small proportion of the variance in cannabis use was related to the polygenic risk score, but quite a small proportion. In our study, we've looked at this and we have not found that cannabis use, particularly the use of high-potency cannabis, is related to the polygenic risk score. So I think it is possible that a small proportion of cannabis users are a bit odd, in the same way that some alcohol users are using because of anxiety and depression, but the majority are using alcohol because they like the taste and they have fun with the alcohol.

 

So I think there is a small proportion of the variance which is related to proneness to psychiatric disorder, probably in general. The more interesting question is: who is vulnerable? Because even in our studies of people who start before age 15 and use heavy-duty skunk-type cannabis, over 90% of these people are not going to go psychotic. And when I talk to a young chap who's gone psychotic and I say do you think it could be anything to do with all the cannabis you've been taking, the usually response is, No, it couldn't because all my mates, they smoke just as much as me. But they probably don't have the same pharmacogenes.

 

So just as there are genes that determine our response to medical drugs, I think there are genes that determine your response to recreational drugs. And the initial gene which got a lot of publicity from one of our studies in Dunedin, the Caspi et al. study suggested that the famous Val/Val, a variant of COMT, might increase risk. The subsequent results have been a bit mixed, and we have a sort of weak replication. But two other genes have been much easier to show an interaction, and that is with AKT1 and DRD2, which, of course, is the famous gene for the dopamine receptor that we're trying to block with antipsychotics. And these are both postsynaptic genes.

 

Now usually in psychosis the problems are in increasing production of dopamine, and so most risk factors for psychosis increase synthesis and release of dopamine. But if you look at people who are dependent on drugs, they have low striatal dopamine; the more drugs you take, the more use reset your striatal dopamine low, but Abi-Dargham has shown that even if you have a low striatal dopamine, a little increase in these drug-dependent people seems to push them into psychotic symptoms, whereas the rest of us on that level of striatal dopamine, we wouldn’t go psychotic. So this is consistent with the idea that there is postsynaptic sensitivity and the two genes that we have found to be associated with vulnerability. Again, this is partly the work of Marta Di Forti and partly work of Marco Colizzi; the latter paper is just coming out in Schizophrenia Bulletin.

 

So both of these genes are postsynaptic, so it may be that the drug-using psychotic people have a sensitization of the receptor. And this has some implications for their treatment, because if you take people who are psychotic and give them a dopamine blocker, you're doing that because they have high dopamine. But in the drug-related psychosis, they already have low dopamine, which is one of the reasons they have a craving for more drug. If we then give them a dopamine blocker, there's some evidence that you're actually increasing their craving. The drug which is best for drug-induced psychosis is clozapine, because it's not such a high dopamine blocker, and it doesn't push them into more use of drugs.

 

So I think cannabis-related psychosis is important because it's of public health significance, but it also is important because the drug-induced psychoses are the best window into understanding psychosis as a whole. Why is it some people go psychotic on cannabis, other people go psychotic on amphetamine, other people go psychotic on ketamine? Are they all the same predisposition? An amazing study would be to take a hundred people, give them ketamine and see who goes psychotic, then give them cannabis and see who goes psychotic, and then give them amphetamine. You'd never get it past the ethics committee, but it would be interesting to see whether they have the same predisposition. My bet would be that they don't, and that when we think of the environmental risk factors for psychosis, the different environmental risk factors will be operating against different genes.

 

[transition music]

 

Thank you for listening to this podcast from the Schizophrenia Research Forum. If you enjoyed the podcast and find Schizophrenia Research Forum helpful, please consider supporting us with a donation. We are a small team of freelance editors who strive to provide a well-informed, independent view of the research that could help the millions of people across the globe who suffer from schizophrenia and other psychotic disorders. Help keep us going by visiting our website and clicking on "Support Us" link in our table of contents on the left side of the screen.

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to Editor Hakon Heimer at info@schizophreniaforum.org.

 

[outro music]

 

Jul 28, 2015

Schizophrenia Forum Radio: Episode 3, featuring an interview with Daniel Weinberger, discussing the first five years of the Lieber Institute for Brain Research.

 

 

 

[intro music]

 

 

 

Hello, and welcome to the July 2015 podcast of the Schizophrenia Research Forum. I’m your host, Kate Lohman.

 

 

 

This week’s podcast features an interview with Daniel Weinberger, cofounder and director of the Lieber Institute for Brain Research. We'll talk with him about the start-up of the institute and about where they have placed their bets on finding better treatments for psychiatric disorders.

 

 

 

But first, here is a brief description of the Forum and a summary of some of the latest features you will find online at Schizophrenia Forum dot org.

 

 

 

Schizophrenia Research Forum is in its 10th year of providing news, discussion, and resources about the search for better treatments for psychotic disorders. We were originally funded by the National Institute of Mental Health, and are now a project of the Brain and Behavior Research Foundation, the major private funder of research into mental and emotional disorders. All of our content is entirely open to the public.

 

 

 

Recently we posted two cautiously optimistic stories about drugs that could improve cognition in people with schizophrenia, an area where there has not been much progress.  First, Tarek Rajji and colleagues in Canada reported on a study of the drug clozapine, which does seem to rise above the crowd of antipsychotic medications. Rajji's work, posted to our news section on June 15, supports the idea that working memory is improved when more of the clozapine is broken down into a metabolite called NDMC. This raises the possibility that working memory could be improved more consistently by ensuring that the ratio of NDMC to clozapine is higher.

 

 

 

Another story, posted June 28, describes promising results from a clinical trial of encenicline, an agonist at the alpha-7 nicotinic receptor, developed by Forum Pharmaceuticals. In this Phase 2 trial, people with schizophrenia showed improvement in several cognitive domains when they took the drug. The US Food and Drug Administration viewed the data positively, granting the drug Fast Track designation for follow-up studies.

 

 

 

Finally, we recently held a webinar on the study of schizotypy. Schizotypy is a psychological construct encompassing odd or abnormal thoughts and behaviors, sometimes quite mild, that resemble psychosis. Some researchers think that the genetics and neurobiology that underlie schizotypy could represent a risk state for schizophrenia, making it a valuable focus of study. Our webinar featured an international panel of experts, and you can view the recording and see the presenters slides in the Online Discussions section of our site.

 

 

 

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Now to the interview. Daniel Weinberger spent the bulk of his career at the U.S. National Institute of Mental Health, conducting studies across the spectrum of schizophrenia research, with a particular focus on imaging and genetics. Five years ago, with a commitment of $120 million dollars from the Lieber and Maltz families, he founded the Lieber Institute for Brain Development together with fellow NIMH researcher Ron Mckay [KATE: rhymes with eye] and Johns Hopkins University neuroscientist Sol Snyder. The "Lieber," as it is known informally, is an independent institute, but has affiliations with Johns Hopkins.

 

 

 

Schizophrenia Forum Editor Hakon Heimer talked with Weinberger recently to find out what Weinberger and colleauges have been investigating.

 

 

 

Interviewer – Hakon Heimer

 

Thanks for taking the time to talk.

 

 

 

Interviewee – Daniel Weinberger

 

It's my pleasure. Nice to be with you.

 

 

 

Interviewer – Hakon Heimer

 

Can you give us a brief history of how the Lieber Institute came into being?

 

 

 

Interviewee – Daniel Weinberger

 

I'd be delighted to. So the Lieber Institute for Brain Development and the Maltz Research Laboratories – as an independent, philanthropically founded medical research institution, a not-for-profit 501(c)(3) institution affiliated with the Johns Hopkins School of Medicine – this was the visionary thinking of two families who have been absolutely fundamental to private philanthropic support of mental illness research. This is the Lieber family of New York and the Maltz family of Cleveland, Ohio. Both of these families have been the principals behind the Brain Behavior Research Foundation, which used to be called NARSAD, for over 20 years. And after the establishment of the Broad Institute at MIT and Harvard, which was a massively privately-funded institution study medical genetics, they had become increasingly interested in the possibility that a privately-funded focused research institution – around trying to understand the developmental mechanisms of schizophrenia and related developmental brain disorders – might be appropriate to initiate.

 

 

 

And there were several years of plans, meeting (we had a number of advisory meetings); I had interacted with them around this idea we started these discussions literally 10 years ago. We had many advisory groups meeting, including with a number of Nobel Laureates, where we tried to hash out the idea that we could create a a focused mission oriented, psychiatric research institution, which whose total mission was to use new molecular and genetic information about brain development and about risk for psychiatric illnesses to translate this into new therapies. And the whole idea was to use this novel scientific information – which was really emerging at the turn of the 21st century on psychiatric research – to change the lives of ill people.

 

 

 

That was the mission, that was the purpose after five years of discussions, planning. We interviewed a number of institutions, including Harvard, Yale, Columbia, Rockefeller, University of Pennsylvania, Johns Hopkins. We settled on Johns Hopkins for a variety of reasons; one being it was very close to NIH where many of the founding scientists of the institute came from, which was in Bethesda, Maryland. Two, they had a brand new, state-of-the-art, absolutely gorgeous research building on the main campus surrounded by the Johns Hopkins Medical Center, which made it a very attractive physical space. And then, third, Johns Hopkins – other than being a great medical institution and research institution – had no difficulty tolerating a private institution affiliated with it. In fact, one of the preeminent institutions about brain development at Johns Hopkins is the Kennedy Krieger Institute, which is not like the Lieber Institute for Brain Development. It's not part of Johns Hopkins; it is a private institution affiliated with Johns Hopkins. This gave us remarkable flexibility and efficiency aspects that were we under the institutional control of Johns Hopkins probably wouldn't be as possible.

 

 

 

So that's the origins of the institute. We were founded August 1st, 2010 as a 501(c)(3) institution. We had a small operating group here for the first year of operation while we built out our laboratory and office and technological space, which is spectacular, brand new, very dramatic space. And we moved into the space October 1st of 2011. So in a sense, we've been operational, as a research institution, for a little less than four years. That's the history.

 

 

 

Interviewer – Hakon Heimer

 

Did you start building with any one specific project, or did you build in several at once?

 

 

 

Interviewee – Daniel Weinberger

 

So we basically had a model of trying to understand how genes and the environment affect the development of the brain relevant to the risk biology of psychosis, schizophrenia, and related disorders. That was the idea. So with that idea in mind, we felt that there were several key investments that had to be made by the institute to generate momentum early on. The first was…and this had a lot to do with work that myself and my colleagues, particularly Joel Kleinman and Tom Hyde had been doing at the NIH. Which was that if you want to study a brain disorder, which we assumed schizophrenia and autism and even bipolar disorder to be, you have to have brain tissue; you have to study the brain. This may seem like a no brainer to anybody who thinks about this, but the fact is for most of the second half of the 20th century most of psychiatric research was not done on the brain. It was done on things like urine and blood and, you know, and that sort of thing.

 

 

 

So, you know, we started a program at NIH 30 years ago where we said we're going to study the brain because these are brain disorders. So when we got to the Lieber Institute for Brain Development, we felt now that we had the capability to move very efficiently and facilely in this direction we put a major investment in acquiring what is now without any question, you know, a historic collection of human brain tissue. That was the first major investment that we got started doing. I can tell you more about that in a moment. The second major investment was a stem cell biology program. Because if you want to study brain development and its relationship to building the programs that ultimately are malfunctioning in people that have psychiatric disorders, you have to start with the first cells. One of the reasons that genetic discoveries matter is because genetic discoveries are ways to understand what's happening to cells. Genes are the blueprints of the biology of cells.

 

 

 

So how does this all start? It starts with the first fertilized egg; that is the so called pluripotent stem cell that builds all the cells of the body, all of the organs of the body. So we felt it was critical to have a pioneering stem cell biology group focused on understanding how the genes and environmental factors that are associated with risk for schizophrenia and related conditions affect the biology of these early cells. And we recruited Ron McKay, who was the head of the stem cell program at NIH and one of the pioneers of stem cell biology, to lead this group. The third thing that we felt was critical since it was in the mission and the basic genetics of the Lieber Institute for Brain Development and the Maltz Research Laboratories was that we have a drug development program. Because all of this basic science – the genetics, the cell biology, the developmental biology – was supposed to give us clues to a new generation of therapies.

 

 

 

So one of the reasons we came to Johns Hopkins was Sol Snyder  – who was the previous head of the neuroscience department here and a Presidential Medal of Science winner and the discoverer of the opiate receptor among many other discoveries, one of the great figures of neuroscience of the second half of the 20th century – offered himself as a component of the Lieber Institute for Brain Development if it came to Johns Hopkins. Specifically that he would head the drug development program. And Sol has extensive experience in drug development around CNS disorders. So Sol helped us recruit what we think is an exceptional group of people headed by Jim Barrow, who was previously a lead medicinal chemist in CNS drug discovery at Merck. We have a large, very outstanding drug development program. So those were the three principle projects that we invested in from the get-go in the Lieber Institute for Brain Development.

 

 

 

Interviewer – Hakon Heimer

 

I don't hear animal models, and that's something that you were involved in quite a bit in the past. Is that something that you don't see as valuable any longer?

 

 

 

Interviewee – Daniel Weinberger

 

We still think animal models – despite the the casual dismissal of animal models that one reads about from time to time – are extremely important, particularly now that we have genetic mechanisms of risk. Because the animal models allow us to model in vivo biology. What I think people confused about with animal models is that we're not modeling an illness; we're modeling a molecular mechanism of risk and trying to understand how that affects the development and function of living brains. We can't really do this very easily in human beings. So we have three, four drug animal modeling groups here at the Lieber Institute, and they're all headed by NIH funded investigators who were studying specific animal models based on genetics of how genes of interest translate into a system-level brain biology of interest.

 

 

 

Let me make one comment about genes. We don't study the genes per se; we study how these genes are processed in human brain to account for risk. So for example, in our brain project, what is typically done when a gene is discovered is one take a cell – or one takes a mouse – and you knockout the gene, or you knockup the gene. You either increase its activity, or you decrease its activity. We don’t do that. The reason we don't do that is because we've found – has to have other groups, but we've mainly been the leaders in this area – that the genetic risk is not about too much or too little of the gene. It's genuinely about a modification in what the gene actually is. So when you look at how genes are turned on and off and processed in a human brain, you find that in most instances these genes don't look like they look in the textbooks, they don't look like they look in the websites that people go to routinely to identify what a gene actually looks like structurally. Because in the human brain, genes are transformed into many variations from the same region of the genome.

 

 

 

And what we do is we take a gene that's been associated with risk, for example, schizophrenia, and we look in the human brain at what that gene actually looks like, and we find that that gene does not look like it looks in the textbook. Some of it looks that way, but other aspects of it look completely unrelated to the textbook. And what we find often is the risk for schizophrenia or for autism or for bipolar disorder is not about the way the gene looks in the textbook; it's about a particular form of the gene that we find in the brain. That becomes what we do in the cells; that becomes what we do in the animals. So we're not knocking down a gene or knocking up a gene. What we're doing is we're changing the expression of what we call a pathogenic transcript.

 

 

 

The pathogenic transcript is the risk-associated molecular feature, the risk-associated form of the gene that is related to what risk means at a biological level. That's what we do with the cells, that's what we do with the animals. So we are modeling both at the cellular level and in living brain level, which is the animal, the pathology of risk. Because people don't become ill because of a statistic in a population genetic study. No statistic makes somebody sick. You're sick because the biology of what that statistic is leading you towards. So we use the resources at Lieber Institute to identify that biology. That then becomes the starting point for cell models and for animal models.

 

 

 

Interviewer – Hakon Heimer

 

I took a look back at the Science article on your startup, and you said that you wanted to do more "risky work" and interact with industry. And I wondered if you could give me some examples of those things.

 

 

 

Interviewee – Daniel Weinberger

 

Well I mean, again, I think the risky work…by "risky work" what we generally mean is work that would be difficult to get a consensus type study section of an NIH grant to go for it. Because it's generally difficult to do cutting edge pioneering not out, you know, out of the box research these days. So, you know, that…I think most of what I've described is pretty much that. We have been very successful because of this new model, because of the efficiency and flexibility of the Lieber Institute model. And I should point out we have a very diverse faculty here; there are over 100 people now working in the Lieber Institute for Brain Development from 14 countries. Diverse scientific disciplines from computational science, bioinformatics to computer-led science to basic molecular biology, cell biology, molecular genetics, clinical genetics, psychiatry, neurology, systems neuroscience, biomedical engineering, very diverse group of people, over 20 investigators.

 

 

 

And what we've managed to do with the pharmaceutical industry is we have brought them back into the research to find new targets for psychiatric illness because of the model here. And the model is flexibility, not being stuck in having to defend some prior funded idea, which is high risk; we created a I think historic pre-competitive consortium of six drug companies to help us develop for public use data sets related to how genes build the human brain. And this is using the RNA sequencing. In human brain, we're looking at many regions of the brain across many different groups of individuals – normal human beings from early fetal life to age 90 – and a variety of psychiatric disorders. We have six drug companies working pre-competitively together to generate all this data which will go into a public website that anybody in the world will be able to access.

 

 

 

What makes the pre-competitive consortium so unique is not just that we have six drug companies contributing resources to it, but we have the drug companies contributing people to an analytical group who work non-competitively together to build this database. Nobody owns the data; the data is all public. The drug companies are working together without owning the data to have access in realtime to the generation of these data. This I think is unheard of example of how this model can generate this kind of interest and response. We have also built collaborations with eight drug companies around target development, several major projects. And we're not doing any work for drug companies. We are having drug companies partner with us in the target discovery model of the Lieber Institute for Brain Development. So we think that's an example of bringing…and many of these companies had at least said in public that they were leaving the CNS drug development world because it was too risky, the deliverables were too far in the future, etc. They're back. Many of them are back. We think we've played a role in that.

 

 

 

I should also point out that our drug development program I think has been remarkably fortunate; not just because of the people in it, but because it's had enormous success. We are about one year now from the first in-human trial of a new family of drugs that we believe will have broad clinical application for cognitive disorders and disorders of behavioral control. These disorders include traumatic brain injury, mild cognitive impairment of the elderly, ADHD, schizophrenia, probably early Alzheimer's disease and Parkinson's disease. And we're about one year now from the first in-human trial of a whole new family of drugs that will have been developed at the Lieber Institute that target a very specific enzyme in the brain that we believe is critical to modulate how the human cortex works efficiently in a tuned way. I'm not really at liberty to talk about this because we're in the process of negotiating partnerships around this. But this is I think a really very promising development. You'll hear a lot more about this in the next I would say couple of months.

 

 

 

Interviewer – Hakon Heimer

 

Are there any other areas of really promising research that are not classified?

 

 

 

Interviewee – Daniel Weinberger

 

So I'll give you an example of one of the things we've focused on, and we have a manuscript out for review now for three months in a journal that you've heard of, but I don't want to jinx it. You know, we've taken one of the regions of the human genome called a locus that was identified in the recent large-scale clinical genetic study in schizophrenia, the so called PGC2 study, which was published in Nature a year ago. This was the study of 150,000 people identified 108 regions of the human genome where genes for risk with schizophrenia seemed to reside. And we picked on region, which has 10 genes in it. And you cannot tell from the clinical study whether or not it's one gene that accounts for that signal – that positive relationship to schizophrenia – two genes, four genes, or all ten genes. There's no way of knowing; you cannot tell from the clinical study.

 

 

 

But we could tell because we go into the brain of people, and we say here we have all of these changes in the genetic sequence: the DNA, which found this region of the genome, let's see which of these changes in the DNA sequence account for which of these genes in the human brain. And what we found was all of these variants across this genome account for only one gene, and none of the other 10 genes have anything to do with this signal. So we've identified what the gene is that accounts for this signal. And the gene happens to be a weird enzyme called arsenic methyltransferase. None of the other 10 genes in that region have anything to do with the clinical genetic finding of this region being a risk region for schizophrenia in the human genome. So all about this arsenic methyltransferase, which is totally weird because why would a drug that makes arsenic less toxic to you – arsenic is a toxic, heavy metal in many foods – why is this enzyme related to schizophrenia?

 

 

 

So we do what I mentioned earlier; we looked in the human brain at this gene. And we discover that actually it's not arsenic methyltransferase, even though that's the gene that the textbooks and our public databases say is what's in this region of the genome. And we discovered in brain that it's actually a completely novel gene and a completely novel protein that's in this region of the genome, but it's not arsenic methyltransferase. We've characterized it very extensively, and we find that this is a unique human protein; it's not found in chimpanzees. It's accounted for by a unique human variation of the genome, which is not the variant found in this big psychiatric genetic study. And we characterized exactly how this novel form of this gene is formed; how it's expressed; and we're exploring this particular form of the gene, which is the pathogenic form of the gene, in a variety of cell, animal and other models to see if we can uncover a way to reverse the effects of this as in brain development function.

 

 

 

This is a completely novel discovery of a risk factor for schizophrenia. It's also a risk factor for multiple other psychiatric illnesses actually. This locus was found in this so called cross disorder genetic association study that included bipolar disorder, ADHD, depression, and autism. We also show that this particular novel gene and protein is turned on very dramatically when early stem cells move toward becoming neurons. So it has something to do with the very early patterning of how a cell decides that it's no longer going to be a stem cell; it's now going to be a neuron.

 

 

 

Interviewer – Hakon Heimer

 

Okay, great. I appreciate it. Thank you.

 

 

 

Interviewee – Daniel Weinberger

 

Anytime.

 

 

 

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Thank you for listening to this podcast from the Schizophrenia Research Forum. If you enjoyed the podcast and find Schizophrenia Research Forum helpful, please consider supporting us with a donation. We are a small team of freelance editors who strive to provide a well-informed, independent view of the research that could help the millions of people across the globe who suffer from schizophrenia and other psychotic disorders. Help keep us going by visiting our website and clicking on "Support Us" link in our table of contents on the left side of the screen.

 

 

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to Editor Hakon Heimer at info@schizophreniaforum.org.

 

 

 

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May 24, 2015

Schizophrenia Forum Radio: Episode 2, featuring an interview with Patrick McGorry of the Orygen Youth Health Program in Melbourne, Australia, on recent research from his group, including an update on the clinical trial of fish oil for the prevention of psychosis.

 

 

 

[intro music]

 

 

 

Hello, and welcome to the May 2015 podcast of the Schizophrenia Research Forum. I’m your host, Kate Lohman.

 

 

 

This week’s podcast features an interview with Patrick McGorry of the Orygen Youth Health Program in Melbourne, Australia, discussing the latest research from his group, including the first data from a much-anticipated clinical trial of fish oil for the prevention of psychosis. But first, here is a brief description of the Forum and a summary of some of the latest features you will find online at schizophrenia forum dot o-r-g.

 

 

 

Schizophrenia Research Forum is in its 10th year of providing news, discussion, and resources about the search for better treatments for psychotic disorders. We were originally funded by the National Institute of Mental Health, and are now a project of the Brain and Behavior Research Foundation, the major private funder of research into mental and emotional disorders. All of our features are entirely open to the public.

 

 

 

Recently, we reported on the first public report of data from the national RAISE study led by John Kane of Zucker Hillside Hospital in Glen Oaks, New York. "RAISE" stands for "Recovery After an Initial Schizophrenia Episode," and the study was designed to offer comprehensive early treatment to people in the early stages of psychosis. This ranged from expert guidance on the right kind and dose of medication, to family support. At a meeting of the U.S. National Advisory Mental Health Council, Kane reported that this kind of care improved self-reported quality of life and boosted work and school participation. People in the program also had a quick improvement in their symptoms, which may have contributed to their ability to return to their regular lives. You'll find this report in the Research News section of our website, published on March 11th.

 

 

 

At the other end of the research spectrum, we posted a report April 7th on DISC1, the most heavily researched schizophrenia risk gene of the past decade. The Kaibuchi lab at Nagoya University in Japan used genetically altered mice to show that DISC1 protein plays a role in mRNA transport. This finding of yet another biological role for the multitasking protein offers a clue that could help us understand schizophrenia and other psychiatric disorders. However, the paper also brought up a long-simmering disagreement in this corner of the research community—Kaibuchi's group suspects that work by other labs is compromised by off-target effects of the methods these other researchers used to knock down DISC1 in animals. We invite you to read and respond to these assertions, along with some vigorous defences of their work by several of the research groups in question.

 

 

 

Finally, we are currently rolling out reports of the lastest research from the International Congress on Schizophrenia Research, which was held March 28 to April 1, in Colorado Springs. You will find the entire list in the spotlight on our homepage, as well as in the Virtual Conferences section. We direct you in particular to the report published April 29th, on a workshop that the Forum helped organize to discuss the future of using animal models to study psychotic disorders. The discussion ranged widely, from models created with lesions of specific brain regions during development to the modeling of genetic risk gene effects.

 

 

 

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Now to the interview. Patrick McGorry of the Orygen Youth Health Program in Melbourne, Australia, may be the most famous psychiatrist in the world. He's certainly the most famous one in Australia, where he was named Australian of the Year in 2010 by his countrymen. He was acclaimed for establishing the HeadSpace program: youth-friendly mental health centers  to help people stay on track before symptoms like anxiety, depression, or psychosis derail them. Researchers know him for his other great accomplishment: helping to create the field of study that is trying to understand how mental illness initially develops and what works best to prevent it.

 

 

 

Schizophrenia Forum Editor Hakon Heimer caught up with McGorry during the International Congress on Schizophrenia Research last month in Colorado Springs. They began by talking about a study led by McGorry's colleagues Ashleigh Lin and Allison Yung, which appears in the March issue of the American Journal of Psychiatry. The article is entitled, "Outcomes of nontransitioned cases in a sample at ultra-high risk for psychosis."

 

 

 

Interviewer – Hakon Heimer

 

What is the background to the Lin study in terms of the percentages of people who transition to psychosis, and can you say something about whether there’s a consensus on the dropping transition rates from studies that were done 10 years ago to the ones that are being done now?

 

 

 

Interviewee – Patrick McGorry

 

Well, when we formulated these criteria over 20 years ago, what we were trying to do was capture an enriched risk for progression to psychosis from a group of people who were already manifesting distress, functional impairment, and were seeking help, and they also had warning signs of a psychosis. And we operationalized those warning signs, and we found that they did predict many hundredfold increased risk of transition to psychosis within the next 12 months or so. And the meta-analyses have now shown that over three years, 36% of people meeting these criteria for this clinical phenotype will become psychotic over a three-year period. So it is definitely what we’d call an ultra-high risk group, or a clinical high-risk group.

 

 

 

But what we’ve also found is that, and this is something the critics of this idea were concerned about and in a way rightly, because they were concerned what about the other two-thirds of the people who didn’t become psychotic? Have they been affected by being drawn into care in some way? And there are two ways they could be harmed. One is by stigma which we haven’t really got much evidence of that as long as it’s done in a good way, and secondly by overtreatment, by premature treatment with antipsychotics. So there was a concern about, as you say, the other group of patients who didn’t become psychotic.

 

 

 

So this study, the Lin et al. study from our group in Melbourne with Alison Yung and other colleagues, basically followed-up patients from all the studies we’ve ever done in this group over a 20-year period; and so the length of follow-up ranges from two or three years to about 13 or 14 years, so quite a long follow-up on average. And what we found was that of the two-thirds that did not become psychotic, most of them either already had an anxiety or depressive disorder, often with substance abuse mixed in or personality difficulties as well, or they developed it in the follow-up period. Many of them had it at baseline when they were seeking help for the subthreshold psychotic symptoms and their general level of distress, but quite a number also developed it during the follow-up period. So only 7% of patients during the follow-up period did not actually have at some point an Axis I DSM diagnosis.

 

 

 

So when people say, oh, this is just a bunch of normal people that are being somehow inappropriately drawn into care, it’s clearly not the case, they have a need for care; it’s not just a need for care around their risk of psychosis, it’s a need for care on its own merits in terms of other syndromes. It also shows that what we should be doing is not just looking at psychosis as the only outcome to influence, but other exit syndromes like depression, anxiety, bipolar, mania, drug and alcohol problems, personality problems; all of these things can really cause a lot of suffering and functional impairment. And the overall thing we should be trying to prevent is a poor functional outcome, you could say, irrespective of transition. And so then the only really key question that we need to work on is, what kinds of help do people need to prevent these different outcomes or this common functional outcome?

 

 

 

Interviewer – Hakon Heimer

 

You don’t read very much about this group, the people who don’t transition to psychosis. Is there a prejudice within the research community about studying these people?

 

 

 

Interviewee – Patrick McGorry

 

No, I think people are very open to studying them actually, but what’s limited the ability to look across diagnostic groups is not just the diagnostic system which had this kind of excessively strong emphasis on the individual entities as if they were very clear-cut. And that’s the criticism of DSM actually, it’s implied that these things are discreet and non-overlapping disorders, which they’re obviously not, but I think also the way research is conducted.

 

 

 

I’m just at the International Congress of Schizophrenia Research right now, and this is a whole group of people, hundreds and hundreds of people working on schizophrenia, but they’re working in a silo; they’re often unaware of what is actually published in other domains of mental health research, like depression or bipolar, so you’ve got the bipolarists and the schizophreniologists and they don’t really talk to each other much, and they’re not even aware quite often about what the other groups are looking at or finding. So I think moving to a much more cross-diagnostic approach to research in mental health is essential to overcome that problem.

 

 

 

So in moving to a cross-diagnostic approach, the NIMH has created a research strategy called RDoC – Research Domain Criteria. This is trying to put current diagnostic thinking on hold and look in a more open-minded way at the different levels of analysis, like symptoms, experience, and then all the different biological markers and other ways of assessing change. So that’s quite a step forward, is very influential in American research. We’ve gone a step further, I would say, by developing a staging model of mental disorders as a heuristic framework for conducting research, trying to make sense of the neurobiology and the biology of mental disorders, thinking that the stage of illness might affect what is happening to the biology just as much as the actual syndrome, and secondly, to conduct clinical trials to reduce the risk of progression to more severe stages of illness, whatever the actual syndrome happens to be.

 

 

 

So going back to the Lin paper, what we would like to do is capture a broader range of risk for a number of exit syndromes, and then study our ability to reduce the risk of progression from perhaps more pluripotential subthreshold states into more discreet categories. So I think a staging approach, it does the same thing as RDoC in terms of allowing the different levels of analysis to be studied cross-diagnostically, but it gives you a framework for treatment research and also making more sense of the actual neurobiology.

 

 

 

Interviewer – Hakon Heimer

 

That’s a good transition perhaps to the study that you’re presenting here at the International Congress on fish oil. A lot of people have looked forward to more benevolent sorts of treatments that you could apply before people have a diagnosis. So could you review briefly the results of that study?

 

 

 

Interviewee – Patrick McGorry

 

Sure. Well, it was based on exactly that idea that if we’re identifying young people at a relatively early stage of illness, such as the ultra-high risk or clinical high-risk state when they haven’t got sustained or persistent psychosis, we should try to offer more benign and safer forms of treatment as the first step. Unfortunately, we see in the real-world a lot of doctors reaching for the prescription pad at this point, because the person’s distressed and struggling, and they don’t seem to have any other options apart from that. So we were trying to create other options that are safer. Obviously, psychosocial treatments are that option, and there’s a lot of evidence from probably about 10 trials now showing essentially that CBT, informed care, psychosocial care, is effective in delaying the onset. There have been studies looking at biological treatments like low-dose antipsychotics, which obviously may work but probably are too risky to use as first-line – I think they definitely shouldn’t be used as first-line – and fish oil.

 

 

 

A study in Vienna conducted by our colleague, Paul Amminger, who’s working with us – and we were part of that study too – but it was conducted in Vienna some years ago, and it showed very dramatic results reducing the risk for psychosis through omega-3 fatty acids, a combination of eicosapentaenoic acid and DHA. And those benefits have been sustained over many years with that cohort of patients; it was a relatively small sample of 80 patients. So, obviously, what we had to do to see if that was a valid, useful finding was to do a replication study, which we’ve just reported on here at the International Congress.

 

 

 

This study was conducted in nine sites in Europe, Asia, and Australia. It was called NEURAPRO as an acronym implying neuroprotection, and it was conducted over about a four to five year period. We completed the 12-month follow-ups recently. We’ve just done a first set of analyses which were done just in time for this meeting. So 304 patients were included in the study, so it’s much bigger, and a multicenter trial comparing placebo versus omega-3 fatty acids on a background of quite intensive psychosocial care – cognitive behavioral case management – so in contrast probably to the Vienna study, the patients got a better background of psychosocial care.

 

 

 

And that seems to have actually changed the pattern a little bit, because we didn’t find such strong results as we found in Vienna, and, in fact, the transition rate for both groups at 12 months was only 11%. There was some evidence that the actual symptomatic dimensional measures, like depression and also functioning, there were trends that they were better at 6 months in the omega-3-treated group, but they didn’t reach statistical significance. So I think you’d have to say at this stage we haven’t found any clear advantage for the fish oil. However, when we’ve looked at compliance, the compliance to the capsules was moderate at best; about 40% of the patients took 75% or more of the capsules, so that weakened the ability to detect the effects of the fish oil as well. We looked at the noncompliant group and put them together with the placebo-treated group, and we did find the trend then for a benefit in terms of transition rates for the fish oil.

 

 

 

So I guess in summary, we think that it’s probably a weaker effect than what we found in Vienna, but there may be some effect, and it might be quite strong in a subgroup which we’re going to look at. We’re also going to look at whether biological measures of having taken the fish oils, such as changes in fatty acid levels in the blood—which will confirm which patients did and did not take it—if that will give us a sharper picture of whether it was beneficial or not. So I wouldn’t say we can write off fish oil as a promising treatment, there’s still a chance that it may be effective in a subgroup who are prepared to take it. But it’s likely that on top of good quality psychosocial treatment, its benefits may be modest.

 

 

 

Interviewer – Hakon Heimer

 

Are there any other either medications or compounds, besides obviously psychosocial treatments, that you’d like to try out in this group of help-seeking people?

 

 

 

Interviewee – Patrick McGorry

 

Yes, and I think there are a number of possible candidates. One is N-acetylcysteine which has been found to be beneficial in patients with more established illness; it’s an antioxidant, so that’s one that people are considering trialing. Low-dose lithium, we did do a study with low-dose lithium some years ago, but it was an open trial and it seemed to be positive, but we haven’t done an RCT on that yet. That would be quite safe because we’d be using very low doses which wouldn’t require monitoring. Lithium is neuroprotective, so that’s the reason for thinking about that. Anti-inflammatories like aspirin would be a very good candidate, and we had a proposal in recently to look at that more carefully. And, finally, I think cannabidiol, or endocannabinoid-related compounds might be useful, because unlike THC, cannabidiol may actually have therapeutic effects in people with psychosis and maybe in other diagnostic categories as well, because it does seem to have anti-anxiety effects in particular. So I think there’s quite a few candidates.

 

 

 

What’s interesting is drug companies seem to be absent from this space; we haven’t seen the big pharmas really continue on in this space even though it’s theoretically very, very promising, and I think that would be great if we could encourage a lot more R&D along those lines because the stakes are very high.

 

 

 

Interviewer – Hakon Heimer

 

Thanks for taking time out from the meeting to talk with us.

 

 

 

Interviewee – Patrick McGorry

 

Thanks very much, Hakon.

 

 

 

[transition music]

 

 

 

Thank you for listening to this podcast from the Schizophrenia Research Forum. If you enjoyed the podcast and find Schizophrenia Research Forum helpful, please consider supporting us with a donation. We are a small team of freelance editors who strive to provide a well-informed, independent view of the research that could help the millions of people across the globe who suffer from schizophrenia and other psychotic disorders. Help keep us going by visiting our website and clicking on "Support Us" link in our table of contents on the left side of the screen.

 

 

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to Editor Hakon Heimer at info@schizophreniaforum.org.

 

 

 

[outro music]

 

 

 

 

 

Mar 20, 2015

Schizophrenia Forum Radio: Episode 1 with Carol Tamminga and Chuck Schulz on the history of the International Congress on Schizophrenia Research and a preview of this year's meeting, March 28-April 1, in Colorado Springs

 

 

 

[intro music]

 

 

 

Hello, and welcome to the inaugural podcast of the Schizophrenia Research Forum. I’m your host, Dan Keller.

 

 

 

This week’s podcast features an interview with Dr. Carol Tamminga and Dr. Chuck Schulz about the history and highlights of the International Congress on Schizophrenia Research. But first, here is a brief description of the Forum and a summary of some of the latest features you will find online at schizophrenia forum dot o-r-g.

 

 

 

Schizophrenia Research Forum is in its 10th year of providing news, discussion, and resources about the search for better treatments for psychotic disorders. We were originally funded by the National Institute of Mental Health, and are now a project of the Brain and Behavior Research Foundation, the major private funder of research into mental and emotional disorders. All of our features are entirely open to the public.

 

 

 

Here's an example of our work: Earlier this year, the journal Molecular Psychiatry published an article calling into question the existence of hybrid dopamine receptors consisting of both D1 and D2 subtypes. If this turns out to be correct, it would put the brakes on one of the few new avenues of research into new drugs for treating psychotic disorders. If you visit our website, you can read our news summary and the debate surrounding the paper, as well as suggestions for how the controversy could be resolved. You'll find this particular topic in the Research News section, published on January 15.

 

 

 

On February 24, we published a news story that addresses the controversy about whether antipsychotic medications harm the brain. Some of the most innovative research of the past few years involves brain imaging studies that follow people who have recently been diagnosed with schizophrenia. In one of the new studies, researchers confirmed previous findings that medication could be causing shrinkage in some brain areas. But paradoxically, those same people had brains were functioning more efficiently and their cognitive function was better than people who did not take medication.

 

 

 

And going a little further back, we point you to the paper of the year—indeed, many would call it the paper of the last 100 years—in schizophrenia research. Last summer the Psychiatric Genomics Consortium published a landmark paper in the hunt for the genetic causes of schizophrenia. The large international collaboration was able to study more than 35,000 people with the disorder, and established more than 100 regions of the genome that contribute to risk for schizophrenia. As with most mental disorders, research has been hampered by a lack of pathological evidence, but we now have some genetic clues to follow up. You will also find this report, and the discussion about it, in the Research News section of the website, posted July 21, 2014.

 

 

 

[transition music]

 

 

 

Now to the interview. Dr. Carol Tamminga is Chair of Psychiatry at the University of Texas Southwestern Medical Center in Dallas, and Dr. Charles Schulz is Chair of Psychiatry at the University of Minnesota in Minneapolis. We caught up with them in the busy final weeks of preparation for the International Congress on Schizophrenia Research in Colorado Springs. This year marks the last year that they will direct the Congress, which they founded in 1987. We were interested to get their thoughts on how the field has grown since that first meeting.

 

 

 

Interviewer – Dan Keller

 

How many people were at that first International Congress in 1987, and how many do you expect this year?

 

 

 

Interviewee – Chuck Schulz

 

At the first meeting, which was in Clearwater, Florida, there were 176 people who showed up to the meeting. It was really one of the first international and I think one of the very early ones in the United States. There have been meetings since about the fourth one where there have been more than 1000 people at the meeting. And we're thinking that we'll have a little over 1000 again this year in Colorado Springs at the Broadmoor.

 

 

 

Interviewee – Carol Tamminga

 

When we first started – because we were not very well known – half of those 176 people were invited and paid for by us. So there wasn't a big active group doing research in schizophrenia there who wanted to get together and talk with each other. But between 1987 in those 176 people, the 1000 or 1200 people we get to come to the meeting now are all dedicated and focused people working on schizophrenia research.

 

 

 

Interviewee – Chuck Schulz

 

For a number of the recent meetings, also half of the people at the meeting are from outside the United States, so it really does illustrate that it is the International Congress.

 

 

 

Interviewee – Carol Tamminga

 

And this is a meeting where the attendees are very diverse; whereas most everybody at the meeting does schizophrenia research or psychosis research, there probably are about two-thirds of the people who do clinical research and about one-third of the people who do basic science research. In addition to that, we always have some scientists who come from outside of the field to talk about how science in their field is going. For instance, one person this year is coming to talk about autism genetics. And that topic of autism genetics will really be informative about directions of genetics within schizophrenia.

 

 

 

Interviewer – Dan Keller

 

New tools and techniques have come along in those years allowing you to look more deeply in things that you never could probe before.

 

 

 

Interviewee – Carol Tamminga

 

Exactly. That's a very important concept. And we try to enrich this meeting by inviting people from the outside into our meeting and really getting people who are in the middle of doing schizophrenia research to have a real advantage in listening to and interacting with these people.

 

 

 

Interviewee – Chuck Schulz

 

At the very first meeting, Carol and I made sure that we invited scientists from outside the field of schizophrenia in the area of things like genetics, brain development, basic neuroscience, and it has been a theme throughout the meeting, especially with our opening speakers. And I think that that has helped our field, but it has also helped the enthusiasm of the attendees.

 

 

 

Interviewee – Carol Tamminga

 

Another focus of the meeting has been on young people and on building knowledgeable brain based group of clinical and preclinical researchers in the field.

 

 

 

Interviewer – Dan Keller

 

Since that first meeting in 1987, can you put your finger on two or three highlights from those meetings over the years? And did they result in furthering our understanding of schizophrenia or in clinical advances?

 

 

 

Interviewee – Carol Tamminga

 

One of the emphases we've had over the course of several of these meetings has been an emphasis on genetics and new methodologies for genetic research and findings. And actually that emphasis on genetics has really flowered into the presentation at the last meeting by the Psychiatric Genomic Consortium of really their latest and most extensive findings in schizophrenia genetics. And those have been very interesting. There's a long way to go. Even though progress occurs and speeds progress isn't often like lightening. But nonetheless, the idea of having places in the human genome to look for genes that are important for schizophrenia is terrific.

 

 

 

Interviewee – Chuck Schulz

 

At the first meeting in 1987, there was a presentation on the initial response of patients to clozapine. And that was a medication that assisted people that were not responding to the first line of their treatment. But in addition, it also did not lead to any movement disorders, and so that presentation showing its usefulness then also led I think to the development of the atypical antipsychotic medication field.

 

 

 

Interviewee – Carol Tamminga

 

The International Congress was really one of the forums for all of the new drugs – the clozapine like drugs and the second-generation other drugs – to really demonstrate what their clinical efficacy was. And all of that happened through the 1990s and the early 2000s. So that was a big emphasis on the International Congress.

 

 

 

Interviewee – Chuck Schulz

 

We will have that session again this year, and there will be a presentation about medication helping with cognition, which is really the symptom area most associated with outcome in people with schizophrenia.

 

 

 

Interviewee – Carol Tamminga

 

That's been one of the developments about the disease that's happened during the time of our meetings. Whereas schizophrenia was always thought of as really only a psychotic illness, it's been gradually reformulated as an illness that includes psychosis but not limited to psychosis but other cognitive disturbances, as well. And in fact, that emphasis has become so prominent that we have a whole special tract now – a Cognition Tract – within the International Congress, and that's going to be a very active tract this year.

 

 

 

Interviewer – Dan Keller

 

We've gone a little bit over our history. How have schizophrenia research, treatment, and rehabilitation changed over the course of your careers not only since the meeting has been in existence but as you've seen the field develop?

 

 

 

Interviewee – Carol Tamminga

 

People would focus on schizophrenia in individuals who'd had the illness for 30 or 40 years. And they would characterize the symptoms and study treatments in people who were between 30 and 50 years old. One of the big changes in the field now is the reorientation towards looking at very early stages of psychosis and looking at the early transition into psychosis. In fact, Chuck has done a lot of research in this area himself.

 

 

 

Interviewee – Chuck Schulz

 

As Carol mentioned, we are going to be having an area of looking at cognition, but the other area will be the prodrome as well. And that's the name for people with not specific psychotic symptoms but about a third develop schizophrenia. And there will be some reports at this meeting of the characteristics and some of the thoughts about interventions.

 

 

 

Interviewer – Dan Keller

 

In much of medicine, there is a dogma that if you intervene early you will have better outcomes. Is that true in here, as stepping at this prodrome stage?

 

 

 

Interviewee – Carol Tamminga

 

So that's what people think. I mean nobody has really demonstrated that for sure, but it makes a lot of sense, and that's really the focus of the prodrome in the early intervention programs. In fact, we'll have the first report at the International Congress this year, Chuck, of the national rise data, which is the first episode study report.

 

 

 

Interviewee – Chuck Schulz

 

Yes, we will. And it's going to be a really nice symposium because we are finding that in the United States we're pretty much behind other countries in early identification, and those other countries are showing us that the earlier the intervention the better outcome. So we're I think pretty enthusiastic about that part of the meeting.

 

 

 

Interviewer – Dan Keller

 

I guess that is not a research advance, but it's an advance for practitioners in the US to pick up on what other people are doing. But what you see are the big current directions that you think hold the most promise for improving outcomes, Chuck?

 

 

 

Interviewee – Chuck Schulz

 

What we are taking a look at is that this is an illness that is heterogenous, as Carol commented on earlier, regarding the genetics. And I think we have to really start thinking about the subtypes and perhaps how long they have had their illness in order for us to be able to improve our outcomes. I think the next area is that in the treatment – and especially focusing in the early stages – there are a lot of people taking a look at cognitive behavior therapy and now cognitive remediation. Kind of like Lumosity where people with schizophrenia will be working with the computer and their cognition and their functioning is improving. Carol could probably comment on our application of our basic research and how that's going to help us out.

 

 

 

Interviewee – Carol Tamminga

 

Over the course of the last 20 or 30 years concurrent with our meeting, the field of basic neuroscience has just burgeoned, it's just really broke lose. Whereas at the beginning of our careers, Chuck and I drew the brain as a black box now we really know a lot about how the brain functions, and we know a lot about what are the genes, what are the cells, and what are the circuits that contribute to behavioral functions of the brain. This means that when we make clinical observations in people with schizophrenia and people with other kinds of psychosis we understand which are the brain regions that manifest the various kinds of symptoms that we see in schizophrenia. So we kind of know where to go in the brain to look for pathophysiology in schizophrenia, and we'll really be seeing actually pathophysiology developed from human brain tissue, developed from people who have schizophrenia that will inform our progress in the future.

 

 

 

Interviewer – Dan Keller

 

It seems like this is the perfect time for genetics, metabolism, physiology, pharmacology, and imaging to come together in sort of a big matrix or gemisch.

 

 

 

Interviewee – Carol Tamminga

 

That's exactly right. I have one more thing to say about genetics. Most of the research in schizophrenia has been on genetics from the point of view of genomics. And there's another aspect of genetics – or  what we would call epigenetics – and there's a lot of reason to think from people who have already studied the role of epigenetics, for instance in memory disorders, there's a lot of reason to think that epigenetics might be particularly involved in behavioral disorders like schizophrenia. And that's also coming to the fore.

 

 

 

Interviewer – Dan Keller

 

What would you tell people to pay particular attention to at this year's meeting?

 

 

 

Interviewee – Chuck Schulz

 

Well I think that one of the themes of the meeting this year has been the same since the meeting started, and I think for people to participate in the opening lectures each day they will be hearing some just outstanding basic science. I think Carol told you we'd be hearing about genetics, and even if it's in autism it's the sort of talk that really advances our knowledge of neuroscience problems. We do have Kamil Ugurbil, who will be giving talk on the latest update of brain imaging. He works on the Brain Project with the President in this recent new way of working with brain imaging and a number of neurologic illnesses. Carol, maybe you have some suggestions of what people would like to do also.

 

 

 

Interviewee – Carol Tamminga

 

In the first of the day sessions – the first of the day plenary speakers and the first of the afternoon clinical plenary speakers – we get people who are doing advanced studies in the field and who may be heading up areas that everybody should know about for sure and that will be leaders in the field. Our two special tracts this year is one is a Cognition Tract and one is a Prodrome Tract. Oftentimes we also work with the Drug Abuse Institute and look at drug abuse in schizophrenia, which is a big, big problem. So these are kind of tracts that have particular clinical relevance both the Cognition and the Prodrome. There will be – in addition to those – there has been a growing emphasis on human brain imaging and different methodologies not only just a structure but also a function and of connectivity now and using brain imaging in very clever ways to give us information about human brain functioning. And all of those will be amply represented at the meeting this year.

 

 

 

Interviewee – Chuck Schulz

 

So we do have the plenary sessions and we have presentations and posters. I think all of those are just great times and great times for interactions. But we also have discussion groups on one of the evenings. And one of my colleagues has put together one on neuromodulation. And this is an area that's getting started in schizophrenia for noninvasive interventions that we're taking a look at helping people with schizophrenia. So I think people will enjoy that discussion group because I'll sure have a chance to answer questions, make contributions, etc. But it is a nice new area.

 

 

 

Interviewee – Carol Tamminga

 

One of the things that's changed over the years in schizophrenia therapeutics is that, you know, 20 years ago really all of the new drug development was happening in big Pharma companies and that the nation's leaders in pharmaceuticals really made all of the advances in psychiatric diseases and in schizophrenia. These days really a lot of the best advances occur within biotech companies, much smaller companies doing more focused research. And that's been a change that we'll see the fruits of those changes at the meeting this year.

 

 

 

Interviewer – Dan Keller

 

It looks like a very beautiful setting for it: a collegial environment, the right size to interact. So it seems like people will have ample opportunity to interact with plenary speakers and each other kind of out of sessions and in the hallways and in social events?

 

 

 

Interviewee – Chuck Schulz

 

Absolutely. We really have noticed that over the years and lots of attendees have said that's one of the valuable aspects of the meeting.

 

 

 

Interviewee – Carol Tamminga

 

And it also is a time when young people can catch people in the hallway, can catch people perhaps on the way out to dinner or really in some of the discussion sections. And the young people can have direct conversations with some of the more experienced people in the field.

 

 

 

Interviewer – Dan Keller

 

Well I appreciate all of the information, and I hope the meeting is a gigantic success. It seems like it has worked up to this over the years. I looked at the figures; it's grown every year. So this should be no different. You've got more "tools in your belt" at this point than ever before.

 

 

 

Interviewee – Chuck Schulz

 

I think we've…

 

 

 

Interviewee – Carol Tamminga

 

Well put.

 

 

 

Interviewee – Chuck Schulz

 

…developed a little bit over the years. Thank you.

 

 

 

Interviewee – Carol Tamminga

 

Thanks a lot, both of you.

 

 

 

[transition music]

 

 

 

Thank you for listening to this first podcast from the Schizophrenia Research Forum. If you enjoyed the podcast and find Schizophrenia Research Forum helpful, please consider supporting us with a donation. We are a small team of freelance editors who strive to provide a well-informed, independent view of the research that could help the millions of people across the globe who suffer from schizophrenia and other psychotic disorders. Help keep us going by visiting our website and clicking on "Support Us" link in our table of contents on the left side of the screen.

 

 

 

We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to Editor Hakon Heimer at info@schizophreniaforum.org.

 

 

 

[outro music]

 

 

 

 

 

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