Mood
Psychosis in Mania
Dr Kraepelin, tear down this wall.
In mid-2006, at a session of the International Society of Bipolar Disorders conference in Edinburgh, the conversation started to get particularly interesting. Nick Craddock MD, PhD of Cardiff University was discussing genetic susceptibility to psychosis. The gene research, which he and others have been involved in, is pointing to some apparent common ground between bipolar and schizophrenia. Clearly, some "nosological" (diagnostic classification) rethinking was in order.
Various psychiatrists in the audience kept referring to the pioneering diagnostician, Emil Kraepelin. Psychiatrists and others seeking to reform the DSM are leading a sort of "back to Kraepelin" movement that would tear down the artificial diagnostic boundaries now existing between bipolar disorder and what we presently classify as certain types of unipolar depression.
But Dr Craddock was working the other side of the spectrum, and here Kraepelin posed an obstacle. One of Kraepelin’s great achievements was to separate what he called manic-depression (what we now call bipolar and recurrent depression) and dementia praecox (what we now call schizophrenia) into two illnesses. The distinction (what Dr Craddock calls "the dichotomous view") has served psychiatry well over the years, but recent gene studies are beginning to demand a second look.
Then someone mentioned Kraepelin one time too many, and the frustration in Dr Craddock’s response was evident. The gist of his remarks amounted to something along these lines: Why the fascination with Kraepelin? You don’t hear historical figures referred to with such reverence in other branches of medicine. Other branches of medicine work with hard science.
In an article in the June 2007 World Psychiatry, Dr Craddock, with his university colleague Michael Owen PhD, summarily dispatched Kraepelin:
"Theoretical constructs in science, including diagnoses in medicine, have a finite lifespan and should be discarded when the weight of research data against them becomes critical and when more satisfactory alternatives become apparent." A discussion of Kraepelin "is not of direct relevance to contemporary clinical psychiatry."
Rather, Drs Craddock and Owen cited "recent molecular genetic findings," including family studies, a twin study, linkage studies, and association studies.
Concluded the authors:
"Kraepelin … was a clinical scientist capable of major feats of synthesis and demonstrated an ability and willingness to modify his thinking in response to new data. We suspect that, had he lived, he would have abandoned the dichotomous view completely at some point during the 20th century. Further, we think he would have been surprised and disappointed at the failure to move forward in any significant way."
The Double-Whammy Gene
One of the gene studies Drs Craddock and Owen referred to was Neuregulin 1 (NRG1), involved in glutamate signaling. The gene was first implicated with schizophrenia in an Icelandic population. In 2005, Dr Craddock and his colleagues found similar evidence of susceptibility in a bipolar sampling. Further teasing out of the data found that in the bipolar subjects, the effect of the NRG1 gene variation was most marked in cases with predominantly mood-incongruent psychotic features. In the population with schizophrenia, the effect was greatest in the subset which had experienced mania.
In other words, psychosis is not just psychosis. We have psychosis that is linked to mania. We also have what may be best described as "free-floating" psychosis, independent of mania. In their article, the authors suggest that NRG1 may be a sort of double-whammy psychosis gene. Those with the wrong variation are prone to get blindsided by two types of psychosis.
Here’s the rub: The authors point out it is unlikely that other researchers will find corroborating evidence for NRG1 susceptibility if they uncritically follow Kraepelin (and by extension the DSM and ICD). That is because they will be searching for evidence in "bipolar" and "schizophrenic" populations, where the chance of coming across a significant statistical blip is minimal. Instead, the authors suggest, researchers need to think outside the DSM box and study a population that has experienced both types of psychosis.
Schiz Today, BP Tomorrow?
The authors bolster their case with what they refer to as "the G72/G30 (DAOA) locus," also involved in glutamate signaling. Again, the gene was first implicated in schizophrenia, and later in bipolar. But in a large study the authors were involved in, they found an association to bipolar, but not to schizophrenia. What seems to be happening, the authors speculate, is that the variation influences "susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories."
The authors suggest that this gene variation, plus others, could shed light on that diagnostic Hail Mary known as schizoaffective disorder. Very importantly, "these findings also suggest that it is important to take a longitudinal approach to diagnosis and to consider the nature and occurrence of psychotic and affective symptoms across the patient's illness history."
Another way of saying this is that the "bi" in bipolar in certain cases may relate to mood and psychosis. A patient may appear to have bipolar at one stage in his or her life, and schizophrenia in another. The old diagnostic labels, the authors point out, merely mask the clinical reality and impede further research.
The Case for Schizoaffective
The authors contend that the current definition of schizoaffective disorder is too narrow to be clinically useful. Instead, it is treated as a glorified "NOS" diagnosis. Compared with the much broader definitions of schizophrenia and mood disorders, "it is inevitable" that the schizoaffective category will seem less reliable to clinicians. This is especially true if clinicians pay little attention to the different ways psychosis presents itself over time.
Despite the lack of respect for schizoaffective, the authors note that "genetic epidemiology supports a strong genetic component to schizoaffective illness." Based on their findings, the authors suggest the concept of "schizoaffective spectrum phenotype" (SASP). SASP would denote an illness meeting one of the following criteria: 1) DSM-IV schizoaffective disorder, bipolar type, or 2) DSM-IV schizophrenia with at least one episode of DSM-IV mania during lifetime or 3) DSM-IV bipolar I disorder with psychotic features in at least half of all episodes of major mood disorder.
Ironically, "given the lowly status accorded to ‘schizoaffective’ cases in our current official classifications, it would be an embarrassment if genetic and other biological risk factors turned out to have the greatest impact on schizoaffective spectrum illness."
Fare Thee Well, Dr Kraepelin?
Drs Craddock and Owen note that in Kraepelin’s time, with no effective treatments available, the practical aim of diagnosis was to merely predict prognosis. The authors argue that "given that the main goal of modern psychiatrists is (or should be) to provide effective treatment, it is our view that the ultimate validator for our diagnostic systems must be treatment response."
Modern genetics and neuroimaging, the authors point out, are allowing us to identify the biological systems involved in disease pathogenesis and their effects on individuals while they are still alive, in different phases of their illnesses and in varying environmental situations. A biologically based diagnostic system may be far from reality, but science is moving us in that direction.
So what do we do with Kraepelin? Psychiatrists who work the depressive end of the spectrum – Akiskal, Goodwin, and others – make a strong case for bringing him back. The dynamics of cycling and mixed states and temperaments, they contend, can only be understood within the context of how Kraepelin framed manic depression back in the early twentieth century. Basically, if we are to move beyond Kraepelin, first we have to get Kraepelin right.
But Dr Craddock, over at the psychosis end of the spectrum, sees Kraepelin as an historical artifact. Which view of Kraepelin is correct? Both are. Maybe.
Coda
In June 2007, Nature published the results of the Wellcome Trust Case Control Consortium’s Genome-wide Association (GWA) Study involving 14,000 subjects, divided by different illnesses into seven groups of 2,000 and matched against 3,000 healthy shared controls. Advances in gene mapping (with the recently published "HapMap"), gene chip technology (the Affymetrix GeneChip 500K Mapping Array Set), plus the huge sample size offered researchers opportunities previously unavailable in earlier gene studies. More than 50 research groups participated in the study, among them Dr Craddock’s Cardiff group investigating bipolar.
The article noted that "increasing evidence suggests an overlap in genetic susceptibility with schizophrenia."
Further Insight
Carol Tamminga MD of University of Texas Southwestern Medical Center in Dallas is a schizophrenia researcher. In advance of the DSM-V, scheduled for 2012, she co-chaired a planning project, entitled "Deconstructing Psychosis." At the Seventh International Conference on Bipolar Disorder sponsored by the University of Pittsburgh and Western Psychiatric Institute held in early June, Dr Tamminga explained that there might be something more general in psychosis that crosses diagnostic boundaries and that looking at dimensions of disease (such as psychosis) might be a better way of finding genes and biomarkers, plotting out response, and identifying elements of pathophysiology.
Unfortunately, bipolar researchers and schizophrenia researchers rarely talk to each other, despite the obvious overlap of psychosis symptoms. Then came this startling admission:
"It isn’t always so actually easy to say that psychosis is the same construct in these two different diagnoses."
This is because, she explained, the same rating scales are never used, and the same doctors are never used to rate the patients. Yet, the genetic literature reveals a more a lot more overlapping genes between bipolar and schizophrenia than unique genes.
Dr Tamminga is putting together a study comparing patients with schizophrenia to those having bipolar I with psychosis (as well as family members of both groups). Early results show similarities in cognition between those with schizophrenia and those with bipolar I with psychosis, and that "endophenotypal" features such as eye-tracking seem to be similar. The main point of difference between the two groups thus far is that those with schizophrenia experience more psychosis while those with bipolar I with psychosis experience more affective episodes.
During question time, Dr Tamminga referred to a structural imaging study she and her colleagues undertook which found that "the schizoaffective people looked just exactly like the people with schizophrenia."
Deconstructing Psychosis
The American Psychiatric Association, on its DSM-V website, has posted a summary of what took place at the "Deconstructing Psychosis" planning session held over two days in early February 2007. Some highlights:
Dr Tamminga noted that although mood stabilizers alone can treat psychotic symptoms in acute mania, they are not effective in treating psychosis in schizophrenia. Dr Tamminga offered three possible explanations: 1) psychosis has a distinct pathophysiology, common to both schizophrenia and bipolar disorder, and antipsychotics target that molecular mechanism; 2) psychosis is mediated by neural systems which are different in schizophrenia and bipolar disorder, which can be stimulated and treated from multiple points and by many different pharmacologic strategies; and 3) psychosis is a response analogous to "fever" and should not be a primary target for treatment.
Eduard Vieta MD, PhD of the University of Barcelona pointed out key brain differences in individuals with bipolar and schizophrenia, but noted that an association for genetic risk between the two illnesses "is evident in volume loss in white matter in frontal and temporo-parietal areas." Dr Vieta observed that the presence of affective symptoms in schizophrenia and psychotic symptoms in bipolar suggests that both illnesses lie along a continuum ranging from schizophrenia to schizoaffective depression to schizoaffective bipolar to bipolar I.
Dr Vieta also noted that the absence of psychotic symptoms in diagnostic criteria for bipolar "reinforces the notion that psychosis is a core feature of schizophrenia but not bipolar disorder."
Robin Murray MD of the Institute of Psychiatry (London) noted that given a background of shared genetic disposition to psychosis, individuals with schizophrenia are subject to additional genetic and early environmental disasters that impair neurodevelopment. Dr Murray suggested that psychosis be re-termed "dopamine dysregulation disorder,"
Francine Benes MD, PhD of Harvard speculated that environmental genes are regulated by pre-natal or post-natal stress, and that susceptibility genes that are turned on or off in adolescence. GABA neurons are common sites for cellular and molecular abnormalities in both schizophrenia and bipolar. "The endophenotypes for schizophrenia and bipolar disorder probably involve changes in specific gene clusters within specific subpopulations of GABA neurons."
Following the presentations, the gathering broke out into two groups. The first group recommended (among other things) replacing the current categories with a "general psychosis syndrome" that would cover schizophrenia, schizoaffective, delusional, and brief psychotic disorders, bipolar disorder, and psychotic depression, and reducing the criterion for schizophrenia from six months to one month.
The second group would keep the bipolar/schizophrenia distinction, but urged the possibility of more subcategories (with a pressing need to improve the definition of schizoaffective) and the need for a dimensional approach to psychosis and mood disorders.
The full presentations will be published at a later date.
Final Word
It was one of those knock me over with a feather moments. Flicking through the DSM-IV can do that to a person. The DSM indicates that a manic episode may have psychotic features, but nowhere is a definition offered for manic psychosis. Those seeking an explanation for psychosis must go to the section, "Schizophrenia and Other Psychotic Disorders."
Similarly, the DSM criteria for bipolar depression are exactly the same as the criteria for unipolar depression, creating the erroneous impression that unipolar and bipolar depression are somehow always the same. This is no mere academic argument. Our outcomes, and possibly our lives, are riding on our clinicians making the right call and treating us accordingly.
Has the DSM similarly erred for bipolar psychosis? If so, will the DSM-V catch the mistake? Or is the research lagging too far behind to inform the next DSM? No doubt, the DSM-VI (but probably not the DSM-V) will be state-of-the-art on the topic, but that is cold comfort to us struggling with our illness right now.
Feb 10, 2008
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