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Updated 14 April 2006 E-mail discussion
Printable version

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


Nick Craddock

Mike Owen

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Like many other researchers and clinicians, Nick Craddock and Mike Owen of Cardiff University in Wales feel that the traditional boundaries of psychotic and mood disorders may be getting in the way of progress in basic research, particularly genetics. In the past year, they have published a series of papers, both theoretical and experimental, that argue for moving beyond the Kraepelinian dichotomy of schizophrenia and bipolar disorder as distinct disease entities.

On May 15, 2006, Craddock and Owen led us through a live online discussion of these issues, with an eye toward finding alternative approaches to diagnosis and classification. Mayada Akil of the National Institute of Mental Health served as moderator. Please read the edited transcript, two recent review papers (full text can be accessed by clicking on the journal images above), and the text below and continue this discussion by offering comments.

View Transcript of Live Discussion — Posted 27 June 2006

View Comments By:
Gunvant Thaker — Posted 24 April 2006
William Carpenter — Posted 28 April 2006
Avi Peled — Posted 7 May 2006
Mario Maj — Posted 8 May 2006
Patricia Estani — Posted 10 May 2006
Ian Brockington — Posted 12 May 2006
Avi Peled — Posted 13 May 2006
Assen Jablensky — Posted 13 May 2006
Robin Murray — Posted 14 May 2006
Avi Peled — Posted 15 May 2006
Herbert Meltzer — Posted 15 May 2006
Wayne Fenton — Posted 15 May 2006
Carol Tamminga — Posted 15 May 2006
Francis A O'Neill — Posted 24 May 2006
Karl-Ludvig Reichelt — Posted 29 May 2006
Kiumars Lalezarzadeh — Posted 18 June 2006


Background

by Nick Craddock and Mike Owen

It has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent Emil Kraepelin's traditional dichotomous classification of the so-called "functional" psychoses and form the basis of modern diagnostic practice. However, findings emerging from many fields of psychiatric research do not fit well with this model. In particular, the pattern of findings emerging from genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories, including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. The emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continue to rely heavily on the traditional Kraepelinian dichotomy.

The aim of this Schizophrenia Research Forum discussion is to discuss the current utility, or otherwise, of the Kraepelinian dichotomy for research and clinical practice and consider this against alternative approaches to diagnosis and classification. To focus discussion, two specific issues will be addressed, in the form of questions:

1) Do the disadvantages of the Kraepelinian dichotomy now outweigh the advantages?

2) What are the best alternative approaches to diagnosis and classification? (e.g., dimensions, alternative categories, prototypes.…)

References:
Craddock N, O'Donovan MC, Owen MJ. Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull. 2006 Jan;32(1):9-16. Abstract

Craddock N, Owen MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry. 2005 May;186:364-6. Abstract


Comments on Online Discussion
Comment by:  Gunvant Thaker
Submitted 23 April 2006 Posted 24 April 2006

Nick Craddock and Michael Owen in their editorial in the British Journal of Psychiatry, and both authors with Michael O’Donovan in their recent review paper in Schizophrenia Bulletin, present an interesting and convincing set of arguments supporting the presence of an overlap between schizophrenia and bipolar disorders (Craddock and Owen, 2005; Craddock et al., 2006). Even though the diagnostic dichotomy has been debated ever since Emil Kraepelin proposed the distinction between dementia praecox and manic-depressive insanity, this discussion is very timely in view of recent genetic findings.

Craddock and Owen present four sets of evidence summarized in their two papers: 1) there is familial co-aggregation of schizophrenia and bipolar disorders; 2) a recent twin study that was not constrained by diagnostic hierarchal method showed overlap in genetic susceptibility (  Read more


View all comments by Gunvant Thaker

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 27 April 2006 Posted 28 April 2006

Very important topic coming at a good time. Over the next five years we will have the task of formulating classification and criteria for DSM-V. I have a responsibility for psychosis and schizophrenia, and anticipate substantial interest in pathologic domains which identify subgroups within each major diagnostic class, and determine how these domains cut across diagnostic lines. In regard to the genetic vulnerabilities, it is difficult to imagine entirely distinct "genetics" for similar psychopathology found in different disease classes. It seems to me more likely that a domain such as restricted affect breeds true than a diagnostic class. If restricted affect is common in schizophrenia, but less common in some other disorders, it will bias schizophrenia towards "breeding true." But restricted affect (in this example) would be the psychopathology of interest. What will it mean for classification if we find that genetic vulnerability for restricted affect in schizophrenia is the same as found with restricted affect in other psychotic disorders? I think it will mean a great deal...  Read more


View all comments by William Carpenter

Comment by:  Avi Peled
Submitted 5 May 2006 Posted 7 May 2006

Allen Frances, the chairperson of the task force that produced DSM-IV, and Helen Egger have written, “We are at the epicycle stage of psychiatry where astronomy was before Copernicus and biology before Darwin” (Francis and Egger, 1999). This is so true when you consider our current levels of discussion, for example, in this online discussion. I apologize if this saying seems provocative but it is time for psychiatry to go beyond its primitive current state. We are still debating mental disorders at levels which have no future; at the molecular level we talk about genes and try to understand the level of emergent properties from whole-brain organizations, that is, symptoms. In between genes (molecular level) and symptoms (emergent properties from whole-brain organizations) there are 1010 neurons, each connected (nonlinear transmission) with 107 connected neurons. This level of synaptic neural network is ignored, offering a black box for psychiatrists. Frustrating is the fact...  Read more


View all comments by Avi Peled

Comment by:  Mario Maj
Submitted 8 May 2006 Posted 8 May 2006

I think that what we call "schizophrenia" and "bipolar disorder" are the extremes of a continuum of psychotic conditions. At present, bipolar disorder is reasonably well characterized in the two main diagnostic systems, whereas schizophrenia is not. The various mixed and intermediate syndromes have been described on the basis of an artificial balance between the "affective" and "psychotic" components rather than on a careful characterization of what we see in clinical practice (the literature on "cycloid psychoses" is a significant exception).

I think that a dimensional approach is not mature yet. "Positive symptoms" in a typical case of schizophrenia are different from those of a typical case of psychotic depression, and have different therapeutic implications. Therefore, I do not see how a "positive" dimension could be applied in both cases without generating misunderstandings.

In my opinion, in the forthcoming edition of the DSM and the ICD, we should still try to refine the categorical definitions of schizophrenia, bipolar disorder, and cycloid psychosis/bouffée...  Read more


View all comments by Mario Maj

Comment by:  Patricia Estani
Submitted 10 May 2006 Posted 10 May 2006

I would like to express my general agreement with the opinions cited by the authors in both articles. The model of classification that they propose in the second article is attractive and well defined (Craddock et al., 2006). This proposal is a model that adapts the classifications to the new neurobiological theories of psychiatry, especially complex psychiatric genetics.

I think that the current classifications are not useful anymore, not only in a research but also in a clinical sense. They are so phenomenological and so extensive in their repertoire of symptoms. These classifications do not fit with actual advances in neurobiological research in psychiatry, especially with the field of psychiatric genetics.

I think that if the article has any fault, this would be that more emphasis must be placed on the behavioral components of the different disorders. Dr. Gottesman, in his review of the endophenotype concept,...  Read more


View all comments by Patricia Estani

Comment by:  Ian Brockington
Submitted 12 May 2006 Posted 12 May 2006

In my editorial in the journal European Psychiatry (1992, volume 7: 203-207) entitled “Schizophrenia: yesterday’s concept,” I set out the case against this concept. Briefly summarized, it’s a gross oversimplification. It’s a fiction, with no natural (as opposed to socially imposed) boundaries. It has no agreed central principle, since there are three alternative essential or defining features—progression to defect, “nuclear symptoms” (disorders of will and self), and the solipsism (autism) that underlies delusion-formation and thought disorder. Its history is one of semantic wrangles. This half of the Zweiteilungsprinzip is fundamentally flawed, and should be abandoned.

As for the alternative, great progress has already been made in reclassifying patients who used to be termed “schizophrenic.” In terms of categories, there are a number of possibilities, including various types of delusional psychoses, psychoses based on auditory hallucinosis or disorders of will and self, and hebephrenia. A particularly important concept is that of cycloid or acute polymorphic...  Read more


View all comments by Ian Brockington

Comment by:  Avi Peled
Submitted 13 May 2006 Posted 13 May 2006

I agree with Ian Brockington that schizophrenia is yesterday’s concept; still, his alternative remains in the descriptive realm. It is time to have an etiologic diagnosis for schizophrenia and, for that matter, for all mental disorders.

View all comments by Avi Peled


Comment by:  Assen Jablensky
Submitted 13 May 2006 Posted 13 May 2006

Despite an ever increasing volume of research data, the apparent stalemate of the search for specific genetic causes of schizophrenia and bipolar disorder raises doubts about the validity of the dichotomous definition of the clinical phenotypes, leading to proposals to replace it with a unitary clinical continuum of “psychosis.” Given the poor coherence of the clinical, genetic and other biological findings in both schizophrenia and bipolar disorder, such doubts are justified and the critical discussion initiated by Craddock and Owen is timely.

As a prefatory note, I should like to point out that Kraepelin was clearly aware of the extent of overlap between the two broad syndromes when he wrote (in 1920) that dementia praecox and manic-depressive insanity do not necessarily imply distinct pathological processes, but rather indicate different “areas of our personality” affected by a process (or processes) that are primarily genetic. The “disease entity” was a working hypothesis, provisionally based on marked differences in their long-term outcomes, due to be eventually...  Read more


View all comments by Assen Jablensky

Comment by:  Robin Murray, SRF Advisor
Submitted 14 May 2006 Posted 14 May 2006

I largely agree with the argument put forward by Craddock and Owen. The evidence which convinces me that schizophrenia and bipolar disorder are not genetically distinct is 1) the Maudsley Twin study of Cardno et al (2002), whose findings Craddock and Owen cite, and 2) studies of families multiply affected with schizophrenia or with bipolar disorder which show certain similar white matter and ERP abnormalities in both sets of patients and relatives (McDonald et al., 2004).

Assuming the existence of some common susceptibility genes, it is then important to understand why schizophrenia and bipolar disorder are not identical. Neuropsychological and grey matter deficits are much more noticeable in schizophrenia, as are neurological soft signs. When do these differences originate? Cohort studies show that children who later develop schizophrenia have an excess of subtle neuromotor and cognitive impairments. Children who...  Read more


View all comments by Robin Murray

Comment by:  Avi Peled
Submitted 15 May 2006 Posted 15 May 2006

As Assen knows, I agree and support the idea that the current nosology has brought to a halt relevant advancement in the finding of the etiology of these disorders. Other then grouping symptoms diversely or trying to link specific phenomena to a gene (like was popular recently with impulsivity instead of with a DSM-related syndrome) I believe a theoretical framework should reconceptualize for us what mental disorders really are. If this framework is brain-related, obeying our knowledge about the brain as a complex non-linear system, then findings will start to emerge. In such a framework, psychosis is actually a disorder of neural complexity, i.e., a complicated disturbance to the balance between over-connectivity and disconnectivity in the brains of the poor patients. If there is ever linkage from genes to psychosis, it must first be made between synaptic plasticity regulation and the gene, and later on the synaptic disturbance when applied to neural networks spread in the brain will have the clinical explanatory power. Directly it will not work. I have devised a framework...  Read more


View all comments by Avi Peled

Comment by:  Herbert Meltzer (Disclosure)
Submitted 15 May 2006 Posted 15 May 2006

A Concept Foretold—Kraepelin vs. Greisinger
As a longtime enthusiast of the "Einheitspsychose" (Psychose unique, or unitary psychosis) of Wilhelm Greisinger (1817-1869), I am delighted to see the field coming back to this view. My early research in neuromuscular abnormalities, which most people know only part of (elevated creatine kinase activity during acute episodes) started out as a means of understanding the etiology of schizophrenia, but when I discovered that abnormalities in all aspects of the neuromuscular system (neurogenic atrophy, muscle development abnormalities, increased sprouting of subterminal motor nerves to compensate for loss of motor neurons, abnormal neuromuscular junctions, increased motor unit territories) were common to patients with schizophrenia, bipolar disorder, and psychotic major depression, as well as some of their first-degree relatives, I adopted the view that these findings were genetically based, were common to these disorders, and absent in patients with major depression without psychotic features. I did not study bipolar...  Read more


View all comments by Herbert Meltzer

Comment by:  Wayne Fenton
Submitted 14 May 2006 Posted 15 May 2006

I believe findings of shared genetic determinants across psychotic conditions are most consistent with a dimensional view of psychosis in which presence or absence of deficit psychopathology and the deficit syndrome will be a more salient categorical distinction than presence or absence of affective syndromes.

Population-based studies quantify the co-occurrence of schizophrenia and depressive syndromes. In the National Institute of Mental Health Epidemiological Catchment Area Study (ECA), 1.5 percent of the U.S. adult population met criteria for a lifetime diagnosis of schizophrenia (Robins and Regier, 1991). The odds ratio for comorbidity of unipolar affective disorder among patients with a lifetime diagnosis of schizophrenia was 14 (Judd, 1998), indicating a high probability that an episode of unipolar affective disorder will occur in the lifetime of an individual with schizophrenia. Using improved diagnostic methods, the National Comorbidity Study (NCS) yielded a prevalence of schizophrenia of 0.85 percent (66/8,000) (  Read more


View all comments by Wayne Fenton

Comment by:  Carol Tamminga, SRF Advisor
Submitted 15 May 2006 Posted 15 May 2006

The interesting position by Craddock and Owen is one that is supported not only by modern genetic data, but also by pharmacologic and phenomenologic findings. A dimensional approach to categorizing serious mental illnesses is an orientation that should now be further tested to examine to what extent, in epidemiological samples, our psychotic diagnoses have similar and different clinical, biological, and molecular characteristics. The outcome of how we "bin" our information in psychiatry is of great importance to the discovery of the molecular bases for these disorders, and subsequently, to the development of rational treatments.

It is the case that those aspects of illness, no matter what diagnosis, respond to antipsychotic drugs. We have drugs effective for combating psychosis, mood destabilization, depression, anxiety—all dimensions of illness, not diagnoses. It is also the case that discussions with affected persons revolve around what their illness manifestations are, and the diagnosis is not highly relevant to the treatment discussion.

View all comments by Carol Tamminga


Comment by:  Francis A O'Neill
Submitted 24 May 2006 Posted 24 May 2006

There is no doubt that the current classification system for psychosis is largely unsatisfactory, both from a clinical and a research perspective. However, it seems unlikely that at this stage a classification based on findings from genetic studies will be any better. Several genes affect several cortical and sub-cortical structures, interact and influence complex systems within the brain, to produce a series of symptoms that may fluctuate over time. A simple classification system would appear impossible. For research the future is surely to concentrate on symptom complexes and their neurobiological basis. For clinical purposes this may not have the immediate utility of a categorical approach and some updated version of the old system may be the best compromise. The demands of research and clinical work are different and any efficient system will recognize this.

View all comments by Francis A O'Neill


Comment by:  Karl-Ludvig Reichelt (Disclosure)
Submitted 29 May 2006 Posted 29 May 2006

There will never be an end to this discussion as long as diagnosis is based on symptoms and not etiology. In untreated schizophrenia, peptide increases and especially opioids of exorphine type have been found increased (1-5). In depression, as expected because of peptidase decreases (6-8), we find peptide increases and some overlapping in depression and schizophrenia (submitted). In spite of having been confirmed in five different countries, these data are largely ignored.

Because these disorders have a considerable hereditary component, there must be chemical changes. If not, they can hardly have any hereditary basis at all. A hypothesis that explains both etiology and symptoms has been forwarded (5,9) and offers an explanation of the findings to date clinically.

References:

1. Hole K, Bergslien H, Jorgensen HA, Berge OG, Reichelt KL, Trygstad OE. A peptide-containing fraction in the urine of schizophrenic patients which stimulates opiate receptors and inhibits dopamine uptake. Neuroscience. 1979;4(12):1883-93. Abstract

2. Drysdale A, Deacon R, Lewis P, Olley J, Electricwala A, Sherwood R. A peptide-containing fraction of plasma from schizophrenic patients which binds to opiate receptors and induces hyper-reactivity in rats. Neuroscience. 1982 Jun;7(6):1567-73. Abstract

3. idet M et al. (1982) Acta Physiol Hung. 60: 121-127.

4. Cade R et al. (2000) Nutr Neurosci. 3: 57-72.

5. Lindstrom LH, Besev G, Gunne LM, Terenius L. CSF levels of receptor-active endorphins in schizophrenic patients: correlations with symptomatology and monoamine metabolites. Psychiatry Res. 1986 Oct;19(2):93-100. (Unfortunately, they used the term endorphin for opioids that may be exorphins.) Abstract

6. Maes M, De Meester I, Vanhoof G, Scharpe S, Bosmans E, Vandervorst C, Verkerk R, Minner B, Suy E, Raus J. Decreased serum dipeptidyl peptidase IV activity in major depression. Biol Psychiatry. 1991 Sep 15;30(6):577-86. Abstract

7. Maes M, Scharpe S, Meltzer HY, Suy E, Cosyns P, Calabrese J. Lower angiotensin I converting enzyme activity in melancholic subjects: a pilot study. Biol Psychiatry. 1992 Oct 1;32(7):621-4. No abstract available. Abstract

8. Maes M, Goossens F, Scharpe S, Meltzer HY, D'Hondt P, Cosyns P. Lower serum prolyl endopeptidase enzyme activity in major depression: further evidence that peptidases play a role in the pathophysiology of depression. Biol Psychiatry. 1994 Apr 15;35(8):545-52. Abstract

9. Reichelt KL, Seim AR, Reichelt WH. Could schizophrenia be reasonably explained by Dohan's hypothesis on genetic interaction with a dietary peptide overload? Prog Neuropsychopharmacol Biol Psychiatry. 1996 Oct;20(7):1083-114. Abstract

View all comments by Karl-Ludvig Reichelt


Comment by:  Kiumars Lalezarzadeh
Submitted 9 June 2006 Posted 18 June 2006

High prevalence of schizophrenia in cities with high latitudes needs attention when considering "co-morbid" mood disorders, fast or slow cycle bipolar disorder, and seasonal affective disorder (SAD), that is, in relation to hormonal cycles in males and females.

References:

Saha S, Chant DC, Welham JL, McGrath JJ. The incidence and prevalence of schizophrenia varies with latitude. Acta Psychiatr Scand. 2006 Jul;114(1):36-9. Abstract

View all comments by Kiumars Lalezarzadeh

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