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Live Discussion Transcript


Posted 27 June 2006

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Printable version

Live Discussion: New Findings in Psychosis: Breaking Down Diagnostic Barriers

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Attendees/Participants
Mayada Akil, NIH/NIMH
A. G. Alias, Fulton State Hospital
Lars Bertram, Harvard Medical School
William Carpenter, Maryland Psychiatric Research Institute
Laurel A Copeland, University of Texas Health Science Center at San Antonio
Nick Craddock, Cardiff University
Rachel Craddock
Pamela DeRosse, Zucker Hillside Hospital
Patricia Estani, Ministry of Health of Argentina
Jinbo Fan, Broad Institute
Diego Forero, University of Antwerp
Anne Gibbs, McLean Hospital
Irving Gottesman, University of Minnesota
Dilihan Gumus, Cardiff University
Mei-Hua Hall, McLean Hospital
Hakon Heimer, Schizophrenia Research Forum
Perry D. Hoffman, National Education Alliance for Borderline Personality Disorder (NEA-BPD)/Mount Sinai School of Medicine
Tetsufumi Kanazawa, Osaka Medical College
Verena Krause, McLean Hospital
Giri Krishnan, Indiana University
Todd Lencz, Long Island Jewish Medical Center
Douglas F. Levinson, Stanford University School of Medicine
Deborah Levy, McLean Hospital
Maureen Martin, Washington University, St. Louis
Robin Murray, Institute of Psychiatry London
Mike Owen, Cardiff University
Sharilyn Rediess, Johnson and Johnson
Marcella Rietschel, University of Heidelberg
Thomas Schulze, University of Heidelberg
Jean Theberge, McLean Hospital
Ming Tsuang, UCSD

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

Mayada Akil
Welcome everyone. I would like to start by introducing our two discussants: Professor Michael J. Owen is professor of Psychological Medicine and head of the Department of Psychological Medicine, Wales College of Medicine, UK. He is a psychiatrist/geneticist and heads the Cardiff Neuropsychiatric Genetics group, which is one of the largest such groups in the world. His research interests relate to genetic aspects of schizophrenia, bipolar disorder, Alzheimer’s disease, ADHD and dyslexia, as well as the relationship between 22q11 deletions and psychosis. Professor Nick Craddock is a professor of Psychiatry at Cardiff University. He is also a psychiatrist whose research focus is the molecular genetic investigation of bipolar spectrum mood disorders and psychosis. He has a specific interest in using molecular genetics to refine the clinical phenotype. The topic for discussion today is very timely. Drs. Owen and Craddock have published on this topic and two of their papers are available at the SRF discussion background page. Perhaps Nick or Mike can start the discussion by briefly outlining their thesis. While they are working on it participants should feel free to put out any questions or comments they have.

Nick Craddock/Mike Owen
Recent genetic findings add to a large body of other evidence that conflicts with the traditional dichotomy. We believe now is the time to move to different approaches to classification. Does anyone disagree with this view?

Doug Levinson
Clearly the current schizophrenia-schizoaffective-mood disorder definitions will not stand forever, but I am not convinced that we have enough genetic evidence to suggest what different view should be adopted.

Nick Craddock/Mike Owen
Doug, agreed, not enough for a long-term alternative yet. But researchers need to embrace the deficiencies and collect data that allow analysis unconstrained by the current categories.

Marcella Rietschel/Thomas Schulze
We agree that the current classification is not perfect, but caution against rushing into new classification without solid biological backing. Or, do you think we do already have it?

Nick Craddock/Mike Owen
Marcella, Thomas, we are not suggesting complete abandonment of current systems. However, research is currently being impeded by sticking to a concept of disease entities that do not map onto the biology. Researchers must think outside the box.

Doug Levinson
I would oppose using our current state of genetic knowledge to change DSM-V or ICD-11, but I would favor developing a Research Diagnostic Criteria, Version 2 (RDC-2) that would do what you suggest—guide researchers to collect the kinds of data that would better inform future decisions.

Patricia Estani
I think that the dichotomy manic-depressive disorder/schizophrenia is not a good, or a currently sustainable point of view, because this classification does not fit current psychiatric genetics evidence.

Mayada Akil
Mike, Nick, are you recommending retaining the existing diagnostic categories for clinical purposes but changing them for research purposes?

Nick Craddock/Mike Owen
Mayada, most UK psychiatrists actually already treat according to domains/dimensions of psychopathology, that is, psychosis, depression, mood instability, etc. The problem is that the current classifications and regulatory bodies perpetuate an inappropriate and unhelpful myth of distinct diseases.

Doug Levinson
I don't think it helps clinicians to be constantly changing the "official" criteria unless data are very clear—it just convinces the average clinician that the criteria are not very meaningful. The RDC (Spitzer et al., Research Diagnostic Criteria. [1975] New York State Psychiatric Institute, New York, NY) accomplished the goal of getting researchers to collect data (namely, a great generation of family studies) that made it possible to create DSM-III and the ICD-10.

Nick Craddock/Mike Owen
Doug, of course, changing to definite distinct systems every few years can cause confusion. So what we need is an approach that is not misleading about the current understanding, is clinically useful, and helps, rather than hinders, researchers to unravel the biological basis of disorders.

Marcella Rietschel/Thomas Schulze
We agree. All the participants, just by their mere presence today, demonstrate their interest in thinking outside the box. We think that we should employ innovative strategies with the current data we have, such as covariate-based approaches, reverse phenotyping (use genetic marker data to drive new phenotype definitions).

Nick Craddock/Mike Owen
Marcella, Thomas, we agree about the benefits of using genetics for "reverse phenotyping." Indeed, we develop this reasoning in our recent review of COMT in Molecular Psychiatry (Craddock et al., 2006).

Irving Gottesman
Nick, Mike, I hope you are not voting for a return to the notion mid-1850s of a Unitary Psychosis. Kraepelin is not really dead is he?

Nick Craddock/Mike Owen
Irv, no.

Maureen Martin
Like Herbert Meltzer wrote, there are probably unique and common genetic (and environmental) risk factors for these disorders. I think it is too early to replace the nosology—it may still be better to use the old definitions in a research setting and to use these definitions to continue to identify common and separable endophenotypes and genetic risk factors of each classification. This might make linking endophenotypes and genetic risk factors a little easier so we can better dissect these disorders (based on genetic/biological markers) in the future (in another 10 to 20 years?).

Mayada Akil
Nick, Mike, what would that approach look like?

Nick Craddock/Mike Owen
Mayada, pretty well all disease classifications are mixtures of defined pathological entities and more or less well-defined clinical syndromes. Thus, it is to be expected that this will be the case in psychiatry as our knowledge develops. Therefore, we might find some relatively discrete syndromes that have discrete biology but others that are better conceptualized on a continuum.

Patricia Estani
I think that the model that Craddock and colleagues presented in their reviews is not a biologically closed box. Instead, I agree that the new diagnostic classifications must be catalyzed by molecular genetic findings.

Irving Gottesman
Nick, Mike, I hope that "reverse phenotyping" incorporates the strategies of endophenotyping discussed in the first SRF online discussion.

Deborah Levy
Irv, I second that.

Marcella Rietschel/Thomas Schulze
Irving, endophenotypes are a major basis, provided your criteria are held up. But actually, we should not overwhelm clinicians with the rapid changes we are hoping to make.

Nick Craddock/Mike Owen
Irv, of course, endophenotypes are desirable for reverse phenotyping. The question is how best to use them in forward studies.

Marcella Rietschel/Thomas Schulze
We think that it is most important to realize that the classifications are temporary, especially when clinicians try to develop guidelines for how to treat patients with given diagnoses. Otherwise, considering the limited therapeutic options we have, it does not really matter what diagnosis you give to patients. As long as they are treated individually, that means that their symptoms are treated adequately.

Robin Murray
It does matter what diagnosis you give to patients, as many psychiatrists believe that we have treatments for diagnostic entities, for example, antipsychotics for schizophrenia. However, we don’t. Instead, the sensible clinician will use a dimensional approach and treat positive, negative, manic, and depressive symptoms.

Nick Craddock/Mike Owen
Robin, we absolutely agree.

Robin Murray
A major question is whether any alternative classification can rely on genetic or biological markers, or whether the best alternative is to use symptom dimensions based on factor analysis.

Nick Craddock/Mike Owen
Robin, a biological basis is best.

Robin Murray
Nick, Mike, obviously a biological basis is better if the measure is reliable and has some validity. The difficulty at present is that susceptibility genes cannot be said to have been sufficiently confirmed.

Nick Craddock/Mike Owen
Robin, we are not in any way suggesting that the current genetic findings are sufficient to decide on precise alternative. Rather, our argument is that they are sufficient to show that we need to be thinking about the possible alternatives and—crucially for researchers—already analyzing our existing data in ways that cut across the traditional dichotomy.

Doug Levinson
As I understand it, a diagnosis should predict familial aggregation, course, and treatment response. Regarding treatment, it is true that most psychiatrists now medicate psychotic patients as if the schizophrenia-like and mood components should be treated separately. But this does not seem to be true; people with chronic schizophrenia-like illnesses do not seem to derive much benefit from the constant additions of antidepressants and mood stabilizers (except for antidepressants in "post-psychotic" major depression). This suggests that we are not quite ready for a unitary model, and that simply using factor analyses would not improve the situation. Robin, Nick, Mike, what evidence exists that when someone with chronic psychosis develops transient mania-like symptoms, addition of a mood stabilizer is effective, versus optimization of the antipsychotic regimen?

Robin Murray
Doug, my view is that if individuals develop manic symptoms at any point in their illness, then they should be treated for this by a mood stabilizer. Such a view would suggest that schizophrenia-like symptoms can arise out of 1) a primarily affective disorder or 2) a primarily developmental disorder.

Diego Forero
I agree that there is a need for experimental-based conceptions of mental disease classifications (going further from historical DSM-IV definitions). However, a lot of empirical data is required to achieve this purpose (to find shared regions in linkage studies or association with a same genetic polymorphism for bipolar and schizophrenia is only a small part). The Owen and Craddock proposal is a good starting point for innovative and important approaches in the field.

William Carpenter
Nick, Mike, what is the easiest explanation for family pedigree studies suggesting separate diseases and linkage/genotype studies suggesting overlap?

Nick Craddock/Mike Owen
Will, 1) lack of power and 2) starting with extreme phenotype.

William Carpenter
Nick, Mike, so, with good power and average phenotype, do we get more or less overlap between current disease classes?

Nick Craddock/Mike Owen
Will, the studies have not been done.

Doug Levinson
Will, I agree with Robin that genetic association findings are not yet sufficiently confirmed to support nosological changes, and I would say that if you compare the largest schizophrenia (Lewis et al., 2003) and bipolar (McQueen et al., 2005) linkage meta-analyses, as power has increased, the results do not look terribly convergent.

William Carpenter
Nick, Mike, so the studies have not been done. But don't you clearly expect the genotypes to beat diagnostic types and result in falsifying the current nosology? DSM-V is due in about 5 years. When will we know enough to redesign classes? Or do we move entirely to domains? If you have avolition pathology, that's that. If you also have cognition impairment, then that’s that, too, etc.

Nick Craddock/Mike Owen
Will, we are currently undertaking Whole Genome Association (500,000 SNPs) in 2000 BP spectrum case and will have results by end of 2006. This will not give any definitive answer but may well indicate likely possibilities. We agree that aiming to identify domains of psychopathology that map onto biological systems is the way to go.

Diego Forero
A question for Lars: what is your opinion about the use of several disease subtypes for genetic explorations of mental disorders? A real approach to discover specific and minor genetic effects or only a statistical trick (multiple testing)?

Lars Bertram
Diego, I think right now it is both, unfortunately.

Diego Forero
Thank you, Lars.

Nick Craddock/Mike Owen
Diego, Lars, there are approaches to take account of multiple testing. And replication is the acid test.

Lars Bertram
Nick, Mike, clearly, but I think the confusing and often disagreeing "evidence" tells us that the current methods are just not there yet. We hope that our soon-to-be-launched "SchizophreniaGene" database project is going to fill that gap. [Edit. Note: The SchizophreniaGene database, patterned on AlzGene, will debut online at SRF some time later this year.]

Nick Craddock/Mike Owen
Lars, perhaps. But the problem is current studies use categories that do not map well onto the biology. In our COMT review (Craddock et al., 2006) we show that using the wrong phenotype category causes enormous power loss.

Lars Bertram
Nick, Mike, loss in power can be cured by an increase in sample size; meta-analysis is one easy way to do that. Merging or combining phenotypes may lead to spurious results, at least when there is no real pathogenetic connection between them. Some of these efforts may amount to mere "trial and error." I do realize that that's sometimes what it takes, though.

Patricia Estani
I would like to ask Dr Carpenter, if any point of beginning exists in a phenotype's classification, at a behavioral level, which point is the first one? What type of classification could be the first?

William Carpenter
Patricia, explain a little more what you mean by the beginning point. Is this pathology as a dimension which includes normal behavior?

Patricia Estani
At a behavioral level, what kind of classification could be used, for example, in the case of schizophrenia, that would be more adaptable to genetic findings. Into how many categories could we define schizophrenia in the most simple way, at a behavioral level. For example, is avolition a dimension or symptom of a determined symptomatic category? Or do you explain that avolition itself is a category or dimension?

William Carpenter
Patricia, I would break schizophrenia into a number of symptom categories (e.g., negative, reality distortion, disorganization, obsessive-compulsive, motor), a number of cognitive and physiologic phenotypes (some of which are endophenotypes). Each domain would be of interest for study and application in treatment development. But I don't know what "recombinations" would then make sense for a disease classification scheme.

Mayada Akil
Wayne Fenton, in his preliminary comments, raised the question of whether the dichotomy holds up when we consider schizophrenia with deficit syndrome. Any reactions?

Nick Craddock/Mike Owen
Mayada, Dr. Fenton suggested that deficit state was an important variable. We agree. This highlights the need for studies with detailed phenotyping and a longitudinal perspective.

William Carpenter
I would add that one recombination of interest to us is the use of primary negative symptoms to define deficit schizophrenia which looks like a disease entity within the schizophrenia syndrome, separated from other forms of schizophrenia on many clinical features, but also biomarkers and etiologic risk factors.

Nick Craddock/Mike Owen
Does anyone know of good longitudinal data sets that could be used for genetic analysis?

Irving Gottesman
Nick Mike, three cheers for a longitudinal perspective sensitive to the fact that diagnoses/phenotypes will not stand still during a lifetime of variable exposures to stressors and good stuff as well. See Angst for patients with multiple depressive episodes who then develop mania (Angst et al., 2005), and Shields/Gottesman twins at the Maudsley whose initial diagnosis was depression but who on follow-up had clear schizophrenias (Gottesman, I.I. and Shields, J. [1972]. Schizophrenia and Genetics: a twin study vantage point. New York: Academic Press; Clark and Mallett, 1963). And see Odegaard's Norwegian pedigrees with plenty of crossovers among the psychoses (Gottesman and Shields, 1976, Table 6).

Doug Levinson
I think it will take three or four adequately powered (2,000-3,000 cases) whole genome association studies of schizophrenia and of bipolar disorder, and follow-ups to each study, to start to get a clearer picture. I agree with Nick and Mike that new thinking about phenotyping should be developed now and applied to some of these studies. It would be better, for example, to collect all psychoses using a richer phenotyping scheme. But, it is difficult to collect thousands of subjects longitudinally, and it is incredibly difficult to collect truly valid data retrospectively about the temporal course of psychotic, mood, cognitive, etc., symptoms. Perhaps an RDC-2 would serve as a model for efforts to get clinicians to begin recording more information about symptoms over time, or perhaps we can develop better technologies for doing it.

Deborah Levy
Power could be substantially improved by incorporating endophenotypes into linkage/association studies.

Nick Craddock/Mike Owen
Deborah, perhaps.

Irving Gottesman
Deborah, for sure.

Nick Craddock/Mike Owen
Doug, an appropriately constructed RDC-2 is a possible way forward. The crucial issue is to get researchers to collect the same sufficiently detailed information and to think across existing categories. At the moment, conferences have "schizophrenia" sessions and "bipolar" sessions. Not very useful for joined up thinking!

Doug Levinson
I used the term "RDC-2" because I thought that the principle of RDC is worth remembering: instead of trying to embody a single point of view, RDC tried to capture any categories (given that it was a categorical system) that anyone thought were worth studying, letting the future data speak for themselves. (Keep in mind, though, that the RDC did provide many categories for mixed syndromes, none of which has held very well compared with the old dichotomy—we should be prepared for any outcome, even one which is closer to Kraepelin.) An RDC-2 would have to include a purely dimensional approach as well as a variety of syndromal approaches.

Nick Craddock/Mike Owen
Doug, we believe an RDC-2 should be sufficiently flexible to include both dimensional and categorical approaches.

Hakon Heimer
Mike, Mayada, you were recently at a meeting to discuss definitions of psychosis for DSM-V, and some others of you may have been part of that discussion. Were there any useful concepts/objections, etc., that came up in that meeting?

Carol Tamminga
The APA sponsored a meeting to debate the dimensional versus diagnostic approaches to psychotic diseases from multiple perspectives, including genetics, molecular, and pharmacologic. There was considerable enthusiasm for pursuing a dimensional approach to psychosis for the purpose of research into its molecular basis. There was some caution expressed at the idea of fully changing diagnostic boundaries for practical reasons.

Robin Murray
My impression of the DSM-V preliminary meeting was that there was little research support for the present dichotomy but that none of the biologists present was prepared to say that his or her field, for example, genetics, imaging, neuropsychology, etc., would be superior. The only system that has been shown to be superior to categories is a symptom dimension one as demonstrated by Van Os (Van Os et al., 1996). Such a system is readily combined with genetics.

Nick Craddock/Mike Owen
Hakon, there was a majority opinion that it was time to move on. We agree with Robin that the Van Os dimensional approach received favorable reception at the meeting. And I agree with Carol that most were cautious about abandoning the current system for clinical purposes. An important point we would like to make is this: we do not argue that all the current details will prove to be correct. Rather, our comments refer to the big picture. It is clear from genetic findings to date that the dichotomy is 1) unsupported and 2) unhelpful to discovery.

Diego Forero
Lars, when will the initial results of the SchizophreniaGene database be available?

Lars Bertram
Diego, we hope to be presenting the first preliminary data in October or November of this year.

Diego Forero
Very good, Lars.

Mayada Akil
Everybody, since we will be wrapping up soon, please type in any final questions or comments. Note, however, that you can post comments after the discussion.

Patricia Estani
I think that molecular genetics specialists must work more closely with behavioral specialists, like psychologists interested in behavioral genetic applications to psychiatric research.

Diego Forero
A question for Thomas and Marcella: aside from the ethnic differences, what do you think about the differences between the findings of your paper in AJP 2005 and those from the Williams et al. paper in AGP 2006 (Williams et al., 2006; see SRF news/commentary)? I think that it is an interesting point.

Marcella Rietschel/Thomas Schulze
Sorry, Diego, to which differences do you refer?

Diego Forero
I mean the association of DAOA with specific psychosis phenotypes versus major depression.

Marcella Rietschel/Thomas Schulze
Actually, we have found the DAOA associated with schizophrenia, bipolar disorder (especially those with persecutory delusions), panic disorder, and major depression.

Nick Craddock/Mike Owen
Thank you, everyone—an excellent discussion. Apologies for brief answers and erratic typing. Apologies also if we haven't answered some questions. It has been a bit like playing simultaneous chess against world grandmasters!

Hakon Heimer
That's what Irv said after the last one!

Stephen Shanfield
This is such a complex topic that it is worthy of other chat sessions.

Doug Levinson
Thanks!

Ming Tsuang
Thanks. Worthwhile discussion.

Mayada Akil
This was fun. Thanks for coming.

Nick Craddock/Mike Owen
Bye, everyone.

Patricia Estani
It was a good discussion. Good afternoon from Argentina. Until the next discussion, Hakon and Nick.

Diego Forero
Thanks.

Marcella Rietschel/Thomas Schulze
Auf Wiedersehen.

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