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Live Discussion Transcript


Posted 24 May 2007

E-mail discussion
Printable version

Live Discussion: The New Epidemiology of Schizophrenia

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Attendees/Participants
Simge Aykan, Dokuz Eylul University, Turkey
Elizabeth Cantor-Graae, Lund University, Division of Social Medicine and Global Health
Michelle Chandley, Department of Psychiatry Quillen College of Medicine, East Tennessee State University
Brian Chiko, Schizophrenia.com
Alex Cohen, Harvard Medical School
Gillian Doody, University of Nottingham, UK
Claudia Harrington, Johnson & Johnson
Keith Jarvie, Clera Inc.
Dana March, Department of Epidemiology, Columbia University
Eileen McGinn, Hunter-Brookdale New York, New York
Vera Morgan, UWA School of Psychiatry & Clinical Neurosciences, Perth WA Australia
Preben Bo Mortensen, NCRR, Aarhus University, Denmark
Huan Ngo, Yale Medical School, Section of Infectious Diseases
Greg Price, CCRN Perth
Eugenia Radulescu, CBDB/NIMH
Sukanta Saha, Queensland Centre for Mental Health Research
James Scott, Royal Children's Hospital and University of Queensland
Jean-Paul Selten, Department of Psychiatry, Utrecht University, Netherlands
Ezra Susser, Columbia University, New York
Jaana Suvisaari, National Public Health Institute, Helsinki, Finland
Hao Tan, NIMH
Joy Welham, Queensland Center for Mental Health Research
Dieter Wildenauer, Center for Clinical Research in Neuropsychiatry, University of Western Australia
Name withheld, Layperson
Robert Yolken, Johns Hopkins School of Medicine

Note: The transcript has been edited for clarity and accuracy.


Hakon Heimer
Let's start off by having everybody already in the "room" introduce themselves: I'm Hakon Heimer, editor of the Schizophrenia Research Forum.

John McGrath
John McGrath University of Queensland and Queensland Centre for Mental Health Research.

Dana March
Dana March, Department of Epidemiology, Columbia University; glad to be here!

Alex Cohen
Alex Cohen, Dept of Social Medicine, Harvard Medical School.

Jean-Paul Selten
Jean-Paul Selten, psychiatrist and epidemiologist at Utrecht University, the Netherlands.

Claudia Harrington
Claudia Harrington, Manager-Program Coordination, Johnson & Johnson Pharmaceutical Research & Development.

Michelle Chandley
Michelle Chandley, Department of Psychiatry, Quillen College of Medicine, Johnson City Tennessee.

Hakon Heimer
If you haven't chatted before, you'll see that many things can happen at once in the chat room. So, while the rest of you introduce yourselves, I would like to introduce and thank our chat leader, John McGrath.

Huan Ngo
Huan Ngo, Yale Infectious Diseases Section. Hello.

Keith Jarvie
Keith Jarvie, Dir. Drug Discovery, Clera Inc.; Board Chair, Ontario Mental Health Foundation, Toronto, Canada.

Hakon Heimer
In the informal spirit of this event, and because I think most people here are at least acquaintances, I won't go into any length about his biography and work, except to say that John is Director, Queensland Centre for Mental Health Research, in the Land Down Under. He has varied interests in research, but especially a record of work and recent provocative reviews in epidemiology. I'll now turn the floor over to John.

John McGrath
Hi, everyone. Thanks for joining the discussion and many thanks to the folks who have already contributed comments. We have lots of different topics that we can focus on.

Ezra Susser
Ezra Susser, Columbia University; glad to be here.

Vera Morgan
Vera Morgan, Neuropsychiatric Epidemiology Research Unit, University of Western Australia. Hi.

Greg Price
Greg Price, Centre for Clinical Research in Neuropsychiatry, UWA, Perth, WA. Good evening.

John McGrath
Lots of old friends here—should be fun!

Eileen McGinn
Eileen McGinn, student, Hunter-Brookdale.

Name withheld
I am a parent who has a daughter with schizophrenia. Thank you all who are working on solutions in mental health.

Hakon Heimer
Welcome. We're glad to have someone from the "community" sitting in. (Standard disclaimer—we can't discuss individual cases.)

Joy Welham
Joy Welham, QCMHR, Queensland.

John McGrath
Firstly, I am feeling a bit guilty that, as a “true believer” in epidemiology, I might have pushed the need to link epidemiology with neuroscience too strongly in the Archives commentary. Many of the commentators (James Kirkbride, Jean-Paul Selten, Paul Fearon, Dana March, Craig Morgan, etc.), have reminded us of the need for more precise social psychiatry—concepts like the buffering capacity of social capital, the role of social defeat in minority groups, etc. However, I still worry that left to our own resources, epidemiology will get stuck in the “circular epidemiology” phase of ongoing replication studies, with little added value. So, my friends, to start the discussion, will the new clues from social psychiatry be wasted and turned into a modern “season of birth” effect = endless, mindless (= dumb) replication, less work on specific candidate risk factors, etc.… Your thoughts?

Dana March
John, it seems as though we need to pay particular attention to levels of organization in our studies; research at one level of organization can lead to research on other levels of organization. Paternal age is a fine example—we can move down to the biological level from the social level, or vice versa. But, conceiving pathways and mechanisms is key.

John McGrath
Thanks, Dana—pathways are the key, but can social psychiatry provide us with a royal road to pathways.... Is it the best category of observation? Convince me!

Dana March
Moving across levels can be done, of course; observation can be coupled with experimentation—the latter is most easily done at micro levels. So, while social psychiatry may not constitute the Royal Road per se, it provides a much needed compass.

Jean-Paul Selten
I agree with John and the need to link epidemiology with neuroscience. We will have to explain how the environment impacts upon brain functioning or structure.

John McGrath
Jean-Paul and Liza, do you need any more studies showing that migrant status is a risk factor? Can more refined epidemiology studies provide extra clues on mechanism of action?

Elizabeth Cantor-Graae
We know that migrant status per se is a risk factor; we still don't know why.

Jean-Paul Selten
I do not think we need any more. More refined studies are needed indeed, for example, to test the social defeat hypothesis. We need to know whether the subjects from ethnic minority groups who develop psychosis have indeed experienced social defeat (disprove the ecological fallacy).

Dana March
Migrant status may only be important when considering minority status; we do need studies in Western Europe and in other contexts to refine our understanding of mechanisms. What is it about being a migrant or a minority? Is it discrimination by the majority, breaking social ties, material deprivation, etc.? We need competing hypotheses to move forward.

John McGrath
Thanks, Jean-Paul and Liza and Dana. Okay, so we can refine the category of observation to specific categories, but I wonder if it will all boil down to stress = bad for the brain? What is so special about migrant stress?

Jean-Paul Selten
Liza and I believe it is humiliation. We specified the nature of the stressor.

Ezra Susser
My view is that we need better measures of both social/societal and brain/biological factors, and should not focus on one to the exclusion of the other. In terms of social/societal, we find strong effects of being a migrant or minority, but we don't find strong effects of family SES on schizophrenia, which suggests that it doesn't simply boil down to stress. We need to conceptualize and measure the relevant social variable.

Dana March
Not so convinced about stress, but that remains to be seen. Seems like living in a context that is potentially discriminatory or excluding is key. Could be a stress effect on the individual case; could be epigenetic when a mom moves, encounters discrimination, etc. Our power of resolution is limited in some senses, so we have to form theories and hypotheses about these effects. And, of course, measuring social context is key to that.

Jean-Paul Selten
I agree with Ezra. If the stress of poverty were important, we would find millions of patients in the Third World.

Elizabeth Cantor-Graae
Thanks, Jean-Paul. I would like to add that social defeat may be especially important as a stressor, because the brain is formed through contact with other persons. Man is a social being; thus, the social context may be vital for certain processes in the brain.

Eileen McGinn
Yes, I work with immigrants in New York City. Some already speak English, some are asylees with no family here, some are professionals who can reasonably find a decent job, some have found good networks. Their culture of origin also counts.

John McGrath
So the challenge for our field is to refine stress into more types (a taxonomy of stress), and then measure carefully.

Jean-Paul Selten
Yes!

Huan Ngo
If stress and humiliation, then what are the underlying genetics that predispose specific immigrants to develop schizophrenia.

Dana March
John, Jean-Paul, I am wary of pursuing stress exclusively. You don't necessarily see elevated rates of other mental disorders in minorities. We need to think about social exposures that may be particularly psychotogenic—is that necessarily solely stress related?

Vera Morgan
A general comment. The third-generation epidemiological studies are facing the problems of the older first-generation "social psychiatry" studies in which researchers are confronted with the very fuzzy boundaries of the social constructs they are working with. We need better ways of operationalizing these.

Robert Yolken
I would like to suggest that we also consider infectious disease explanations for increased incidence of schizophrenia in immigrants to Europe. While we think that Europe has fewer infections than Africa or Asia, that is not actually always the case. For example, there are a number of viruses which require the high density of European cities or large expanses of agriculture that are not common in most rural areas of Africa or Asia.

John McGrath
Hi, Bob. Okay, lets broaden the discussion to include other factors like infection. I personally feel that it is not politically correct to suggest that biological factors may be the main factors driving schizophrenia in migrants, rather than sociopolitically mediated factors. For example, some groups, when sorted by ancient geographical origin (no need to use confusing term race/ethnicity), have different prevalence of risk haplotypes. This is ignored. Dark-skinned people are more likely to have low vitamin D, and perhaps other biological factors related to nutrition and propensity to infection. Some of these may be downstream from social factors, but some of us are not so comfortable talking about this topic because we risk being labeled “biological reductionists” and can be cast as uncaring, etc.

Jean-Paul Selten
It is good to consider all possible explanations, including biological ones. It seems to me, however, that biological explanations do not fit the data.

Dana March
John, I think about biological mechanisms for social exposures; the evidence points to that—I agree with Jean-Paul.

Elizabeth Cantor-Graae
I think the latest batch of studies on victimization during childhood as a risk factor for schizophrenia is nicely in line with these more "social" theories, although the influence of "biology" can never be entirely excluded. Does it have to be either/or?

John McGrath
Bob, infection will not go away, but I feel we are reliant on banked collections to get traction on these, and they are a limited resource. The PKU/filter paper samples will be a help, as you recently used for T. gondii with Preben Mortensen and colleagues (Mortensen et al., 2007).

Robert Yolken
As far as I know, there has not been a comprehensive study of infectious or nutritional exposures in immigrants, so there are not any data to fit. I think that this is a good area to study. It might also explain differences between what is seen in immigration to different areas—such as to the U.S. as compared to Europe.

Dana March
The associations with infections or nutritional factors are not nearly as strong as associations we see in migrants. We know famine is a risk factor, but it's unclear what nutritional deficiency is at work with that.

Robert Yolken
Also, as stress is a well-known factor which affects the immune system—along with nutrition—these types of approaches are not at all mutually exclusive.

Ezra Susser
Bob, I agree that we should keep our mind open about infections, and other factors, too. Nonetheless, it’s hard to explain some of the current findings, such as findings on ethnic density, except with social explanations.

John McGrath
I can't resist infectious agents as candidates because they are so potentially powerful from a public health perspective. I am not so sure we can eliminate social defeat or childhood trauma, etc. Should we keep looking for candidates that we can do something about, like the drunk looking for his keys under the lamp post?

Claudia Harrington
John, is it not the biological/neurological response from the social trauma that we need to focus on, and is that not the manner to do something about the social aspects?

John McGrath
Yes, Claudia, we have to keep the focus on the neurobiological reactions to social trauma. This can be modeled in healthy controls and patients to a certain extent. But, as we all know, we have a long way to go to understand the role of stress in brain function—a lot of the neuropsychobiology literature has a 1960s feel to it (e.g., cortisol levels, HPA axis etc.). Sorry if this offends anyone!

Claudia Harrington
John, I agree. I think that the psychosomatic aspect of any mental illness is also well ignored and a better understanding of the relationship between the social and the biological is necessary!

Ezra Susser
John, I wonder if you could say something about how the vitamin D story might fit with the current data on immigrants?

John McGrath
Ezra, the vitamin D hypothesis is now strong for rats and mice, but we are still working on human data. The assay needed to measure vitamin D in neonatal dried blood spots is still under development. Also, the vitamin D hypothesis is pitched at prenatal exposures (= second-generation migrants) and I am not convinced about first-generation (= adult exposures).

James Scott
John and Jean-Paul, perhaps the problem is that as schizophrenia is such a heterogenic disorder, there may be so many etiological factors that are involved. Is the problem that the broad psychosis phenotype is encapsulating many different disorders?

Jean-Paul Selten
Sorry, I must leave. Thank you!

Hakon Heimer
Thanks for coming, Jean-Paul.

Vera Morgan
The discussion raises a number of putative risk factors including nutrition, stress, infection. The problem is that many of these are not specific to schizophrenia. How do we, as epidemiologists, deal with this?

Ezra Susser
Vera, I am not sure that we require specificity of effect to find causes. In any case, though, the effect of early prenatal famine is rather specific to schizophrenia, though not entirely specific (e.g., also neural tube defects).

Dana March
John, because we can't eliminate social defeat doesn't mean it and other social hypotheses are unworthy of rigorous investigation. A psychotogenic set of social practices provides a good rationale for intervention! Are we just uncomfortable with social interventions as epidemiologists used to being more proximal to the individual, more biological?

Claudia Harrington
Dana, I agree with you completely. However, there cannot be a separation between the social and the biological aspects of schizophrenia; they are completely interrelated.

Dana March
Claudia, we can tease them apart in studies—focusing on social in one and biological in the other; I don't think we need all-encompassing studies necessarily to answer everything. I think we just need to work closely together, with strong hypotheses, and rigorous methods.

Claudia Harrington
Dana, agreed around the strength of the data, but I think after looking at the individual aspects, the correlation perspective needs to be researched as well. We know that schizophrenia cannot be treated with psychotherapy alone and therefore, the biological aspects of the disease need to be focused on relative to their treatment success!

Dana March
Claudia, the treatment (e.g., antipsychotics) acts at the biological level. At the social level, what we are trying to tease apart is the causes of variation in incidence, a group-level phenomenon. Etiology, at this stage, is distinct from treatment. The point of considering broad pathways is that social environmental factors winnow their way through many levels into the body and act at a biological level. That's where treatment enters the picture.

John McGrath
My friends, I am looking at the clock. Liza reminded us about childhood victimization and trauma. Anyone like to comment on where this slightly controversial field needs to go next? James, do you want to comment?

Huan Ngo
With the complexity of biological and social factors, do we need a mathematical perspective to consolidate all factors into a comprehensive assessment of interconnection and weight of each variable? Otherwise, individual perspectives can be debated for several decades, whereas Wanda is wondering how her daughter is going to get better.

Name withheld
Huan, thank you and all for your empathy to finding the cure. I hope that my daughter can contribute to that end through her participation in research.

Sukanta Saha
Huan, what type of mathematical model are you proposing? Is there anything worked out?

John McGrath
Huan, mathematical models will be essential to understand systems biology, but our understanding is too imperfect at this stage.

Claudia Harrington
Huan and John, I think that trying to use mathematical models will cause too much generalization at this point. There are too many individual factors to lump everything together as one.

Eileen McGinn
Nutrition is important prenatally (famine) and there is emerging and converging evidence about EPA and DHA (omega 3, fish oil) for many symptoms in cognitive, mood, and behavioral disorders.

Elizabeth Cantor-Graae
Can nutritional factors explain the broad range of ethnic minority groups that have been implicated in migrant studies? We have everything from Moroccans to Greenlanders!

Ezra Susser
I tend to believe that prenatal nutrition acts at one point in the life cycle, and the unknown causes of the increased risk in migrants at a later point.

Dana March
Ezra, you raise a great point about timing of exposures and potential pathways.

Elizabeth Cantor-Graae
I agree with Dana (and Ezra).

John McGrath
Everyone, we agree that broad biosocial, etc., perspectives are needed. In his role as devil's advocate, Assen suggests that we have a moratorium on observational epidemiology (incidence, prevalence, course, etc.) (see comment by Assen Jablensky). Will we learn anything new? Anyone like to bite on this hook?

Dana March
John, I'll bite. How can we refine our understanding of timing and type of exposures without the assistance of observational epidemiology? Ethical issues, of course, prohibit us experimenting in the way that we might like to isolate causes and get at etiologic processes. You convince me now.

John McGrath
Dana, we do need to refine exposures. No one has mentioned cannabis yet, but I see this as a reasonable example of epidemiology providing good enough evidence that it is a risk modifying factor...so we need to plan major epidemiology studies that capture this exposure in a more precise way.

Dana March
John, I agree. And, of course, we would need to plan them in the Netherlands....

John McGrath
Dana, the site of future studies—good point. Will we learn much more by looking at the same sites? We have very good population-based data from places like Denmark and Finland, but I crave more studies from India and Ethiopia!

Dana March
John, strikes me that we would need to have a better idea about what it is about cannabis in order to do that. Cannabis is not the same everywhere, and lots of folks smoke cannabis laced with other chemicals (e.g., formaldehyde). How do we work to narrow that down?

John McGrath
Dana, cannabis is a mystery to me, but I am sure it has potential. I was titillated by the potential for COMT and cannabis to show a gene by environment interaction, but I am not sure if this is still holding up.

Dana March
John, not sure either, but glad you raised the issue.

Elizabeth Cantor-Graae
We need more epidemiological input from low-income countries. After all, they have a greater concentration of these putative stressors than we in Europe (and the U.S.) have.

Huan Ngo
John, Elizabeth, low-income countries have more stressors, but they are dying much younger from malaria and tropical diseases and skew the incidence of early adulthood onset of psychosis.

John McGrath
My friends, we only have a limited time left. Does anyone have a burning topic to raise?

Eileen McGinn
Burning topic: multiple comorbidities of medical and psychiatric illnesses, with drug-naive and drug-exposed patients.

Dana March
Eileen, do you mean physical illnesses resulting from treatment of schizophrenia? Diabetes, for instance?

John McGrath
Eileen, physical comorbidity is a topic that is attractive to governments to fund, it has more proximal outcomes, and it may contribute to ultimate causes (perhaps).

Eileen McGinn
Data seem to indicate that there may be biological factors like insulin resistance and inflammation already in place in some people with psychological diagnoses. Of course, treatment-emergent drug adverse effects may make this worse in some people.

Preben Bo Mortensen
Just one oblique comment: My main concern is not whether all these epidemiological signals we are discussing are there, or if they are worthwhile producing. My concern is, how do we move to the level of causality rather than association? I simply think we need to put in more effort on measurement. For example, we need to ask specifically, can the distribution of exposure to a given infection explain the distribution of schizophrenia? Across immigrant groups and back this with data, the same goes for risk genes, etc. It will be a long and difficult process, but without it we will be stuck with speculation.

Dana March
Preben, I agree with you. Problem is the distribution of social factors, for instance, is difficult to get at; we need to refine our conceptualization and measurement of social factors. We need sociologists on board! Cross-disciplinary research is key.

John McGrath
Thanks Preben...moving to the level of causality is central, but epidemiology is hopeless at this level. I worry that unless we build strong links to neuroscience in order to examine specific, fine-grain mechanisms of action, then we will be cursed with ecological studies for decades. Maybe I am too optimistic about the powers of neuroscience...but the more I work with neuroscientists, the more I think they need us to point them in the right direction.

Dana March
John, same for the geneticists.

Preben Bo Mortensen
Thanks, John, but I'm more optimistic. I think we can move to that level; it all depends on the data and samples we can get at and our level of success in bringing epidemiology thinking into more biological fields of schizophrenia research.

John McGrath
Preben, I am energized by your optimism! Your contribution to epidemiology is an inspiration...and your PKU samples may hold the key to many mysteries of schizophrenia.

Preben Bo Mortensen
Sorry, guys, have to go again; thank you very much John, for setting this up.

Dana March
Bye, Preben!

John McGrath
Dana. Yes we need links to geneticists, but I sometimes think that they are as lost as we are...but maybe I have a bad dose of gene envy. There was a commentary in the BMJ several years ago about a “flat earth approach” to looking for genes. The instructions for development are distributed across many domains, only some of which are in the base pair sequence. I think those of us who have been raised on the neurodevelopmental hypothesis have a healthy balance of genes and environment.

Dana March
John, I agree—it's just a challenge, perhaps one attributable to the sociology of science.

Hakon Heimer
All, are there any ways to get this (dynamic) group to join together in efforts that will create traction? Or are any such efforts ongoing that should particularly be encouraged?

Ezra Susser
John, I like Hakon's idea. This has been thoroughly enjoyable, and I'd love to continue to exchange ideas with this group.

Dana March
Ezra, Hakon, agreed.

Ezra Susser
Hakon, John, others, how about another epidemiology discussion, but we could have a specific focus?

Sukanta Saha
I agree with Ezra, specific ideas!

Hakon Heimer
Certainly, regular SRF discussions on epidemiology can be on the menu. Volunteers to lead future chats are encouraged to apply. I read an interview with an inventor who said that his modus operandi was to look for things that "sucked" (yes, he's American) and figure out how to get around that. Is there a value to a future SRF discussion that focuses on institutional or systemic roadblocks (everyone could nominate a favorite) and then trying to find ways to solve one or two? In the gene hunter world, I see, there are always discussions about how to get people to combine their cohorts. Parallels in epidemiology?

Ezra Susser
Yes, there are definitely parallels, Hakon, and this could be useful as well as interesting.

Dana March
Hakon, combining cohorts, bringing together folks from different studies is key to moving forward. Ezra heads a center at Columbia (IMPRINTS) that does just that. Would be nice to have SRF as a forum for those types of ideas.

John McGrath
Hakon and Ezra, can epidemiology get its act together? In his commentary, Paul Fearon reminds us of the crop of first episodes currently being examined for follow-up; closer collaboration between these groups worldwide would not only be informative but also, dare one say it?, relatively cost-effective.

Ezra Susser
Hakon, perhaps you should take ideas for future topics and volunteers for leading them. There might be someone with a great topic and eager to lead a discussion. Otherwise, though, I'd be willing to co-lead one with Dana.

Dana March
John, thank you so much for leading a stimulating discussion. Hakon, will be in touch.

Name withheld
As a layperson, it's awesome to eavesdrop on candid brainstorming. Thanks very much.

Sukanta Saha
Thanks, John and everybody for this warm discussion. It would be nice to attend future forum discussions.

Hakon Heimer
Ezra, as soon as you asked for volunteers, people started leaving the room. ;-) Thanks to all! And especially to John for leading this and preparing the background text. Anyone interested in leading a future discussion on a specific topic, please e-mail me.

Brian Chiko
Hi everyone, this is Brian Chiko from Schizophrenia.com here. I just wanted to offer our assistance to any group doing nonprofit research who needs help recruiting subjects for their studies—we're happy to help. We get over 450,000 visitors each month—many of whom have family members who have schizophrenia.

John McGrath
Brian, thanks for this and great to have your famous Web page crosslinking to SRF.

Ezra Susser
Have to go now. Thanks, John, Hakon, and everyone else—a great and lively discussion.

Huan Ngo
Thanks, John, Hakon.

John McGrath
Hakon. Time to wind up? We Australians are now past midnight!?

Hakon Heimer
Absolutely. Off to bed/breakfast/dinner for everyone!

Joy Welham
Thanks John, Hakon, and other participants for a very instructive (and enjoyable) chat.

John McGrath
Thanks, everyone, and goodnight from Brisbane. Feel free to send more comments or afterthoughts to SRF.

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