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Data Support Kraepelinian Boundary Between Psychotic Disorders

October 9, 2013. Mood disorders with psychosis represent a distinct category from schizophrenia, according to a study published online October 2 in JAMA Psychiatry. Led by Roman Kotov at Stony Brook University, New York, the study re-examined the categories of psychotic illness using information about how symptoms changed over time and long-term outcome. Statistical modeling of these data showed a boundary between mood disorders with psychosis and schizophrenia, consistent with Emil Kraepelin’s original division of psychotic illnesses. The researchers also report that they found no evidence of a third intermediate category, which suggests that schizoaffective disorder, a blend of mood and psychotic symptoms categorized long after Kraepelin, should be lumped with schizophrenia.

The study contrasts with recent findings that place these disorders along a continuum. Though the Diagnostic and Statistical Manual of Mental Disorders (DSM) categorizes these as three separate entities, and Kraepelin’s distinction of schizophrenia as a thought disorder and bipolar disorder as an emotion disorder endures, genetic risk factors do not respect these boundaries, apparently (see SRF related news story). Similarly, the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) has identified points of convergence among bipolar disorder with psychosis, schizoaffective disorder, and schizophrenia: All three shared deficits in cognition and brain connectivity, with schizophrenia patients the most severely affected (see SRF related news story). Grouping these illnesses separately, some argue, may impede progress in finding their causes (see SRF Live Discussion).

But where diagnostic boundaries are drawn in the first place depends on the information used. In the new study, the researchers take into account how symptoms change over time rather than relying on a simple snapshot. The information comes from the Suffolk County Mental Health Project cohort, which has been followed over 10 years after an initial episode of psychosis (see SRF related news story). One measure, in particular—the percent of time a person was psychotic without any ongoing mood disturbance (called the NAP, for nonaffective psychosis)—allowed for the decisive split.

“[T]he authors have convincingly shown that with respect to one key psychopathologic dimension—the NAP ratio—and one key validator—outcome—the idea of a smooth continuum from psychotic mood disorders on one end to severe schizophrenia on the other can be rejected,” writes Kenneth Kendler of Virginia Commonwealth University in an editorial accompanying the study. “There is a difference here in kind and not just in degree.”

One boundary, two categories
Rather than looking at single features of these disorders and applying thresholds to define diagnostic boundaries, first author Kotov and colleagues plotted pairs of features—symptoms on one hand, and outcome measures on another—and looked for natural groupings. A similar method had been tried before but did not turn up evidence for categorical differences among psychotic disorders (Kendell et al., 1980). The new study applied more advanced statistical techniques to evaluate whether the data pointed to a single continuum or clear boundaries among the disorders.

Data on symptom course were obtained from 526 people in the Suffolk cohort over the first four years after initial hospitalization; of these, 413 people were contacted again six years later and evaluated with the Global Assessment of Functioning so the researchers could get a sense of 10-year outcome.

Among the symptoms followed, the NAP ratio was of special interest because the DSM relies on this feature to distinguish between mood disorders and schizophrenia: Someone with at least two weeks of psychosis without mood symptoms receives either a schizoaffective or schizophrenia diagnosis. When the researchers plotted NAP at four years against 10-year outcome scores for everyone, they found a non-linear relationship: As NAP ratios increased, outcome initially declined, but once the ratio hit 20 percent, the relationship bottomed out, with no further worsening in outcome as NAP ratios continued to climb.

The researchers then used curve-fitting techniques to evaluate how non-linear this relationship really was. This confirmed an abrupt transition in the relationship between NAP and outcome, suggesting a categorical boundary between those with little NAP and better outcomes, and those with more NAP and worse outcomes. The drop off occurred at 1.5 percent NAP, equivalent to 10 days of psychosis without ongoing mood disturbances. This two-step function fit the data significantly better than a linear function, arguing that there is a categorical difference between psychotic mood disorders and schizophrenia.

A three-step model with two abrupt transitions fit the data reasonably well, too—something consistent with the current DSM-5 situation that has three separate categories for mood disorders, schizoaffective disorder, and schizophrenia. But the researchers found that the two-step model was slightly better and suggest that, if replicated, schizoaffective disorder might be better grouped with schizophrenia.

Diagnostic agreement
The researchers then tested their 1.5 percent nonaffective psychosis boundary to see if this cleanly segregated people according to their diagnosis. Because diagnoses were given two years after an initial psychotic episode, the researchers relied on the symptom data taken at the two-year timepoint. They found high agreement, with 88.6 percent of the schizophrenia and schizoaffective disorder group in the category of people showing more than 1.5 percent nonaffective psychosis and 97.3 percent of the psychotic mood disorder group showing less than that.

Another symptom—percent of time manic—also showed a non-linear relationship with outcome and was best fit by a three-category model. These consisted of no mania (fewer than 11 days of mania), episodic mania (11 to 394 days), and chronic mania (>394 days). The mania-absent group included most people diagnosed with schizophrenia and nearly half of those diagnosed with schizoaffective disorder. The other two symptoms evaluated—percent of time psychotic and percent of time depressed—varied linearly with outcome and therefore did not demarcate boundaries between the disorders.

Based on their findings, the researchers suggest that schizoaffective disorder is, at its core, schizophrenia with a comorbid mood disorder layered on top. Whether the shared genetic factors turning up between schizophrenia and mood disorders reflect general vulnerability for psychiatric illness, or a twice-unlucky receipt of separate genetic factors will be challenging to sort out. But finding the core features of each disorder should help.—Michele Solis.

Reference:
Kotov R, Leong SH, Mojtabai R, Erlanger AC, Fochtmann LJ, Constantino E, Carlson GA, Bromet EJ. Boundaries of Schizoaffective Disorder: Revisiting Kraepelin. JAMA Psychiatry. 2013 Oct 2. Abstract

Comments on News and Primary Papers
Comment by:  Irving GottesmanAksel Bertelsen
Submitted 23 October 2013
Posted 23 October 2013

Invigorating intellectual and heuristic debate in this Forum is kept alive by the challenging and informed summary of Kotov et al. by Michele Solis. The nagging problem of the status of schizoaffective disorder cannot be concluded by the evidence in hand from this study or others that are more biologically and genetically informed (e.g., B-SNIP data) because none are dispositive, to borrow a term from the lawyers. We applaud Kendler’s erudite and friendly dissection of Kotov et al. (Kendler, 2013) and concur with his conclusion that it would be premature to eliminate the Kraepelinian dichotomy. After all, the Alte Meister did not have access to GWAS or to DTI data from probands and their relatives, and ENCODE (Maurano et al., 2012) could not have been envisioned, either. We hope to supplement the SRF discussion with our twin (Cardno et al., 2012) and Scandinavian experiences (Bertelsen and Gottesman, 1995; Laursen et al., 2005; Gottesman et al., 2010; Lichtenstein et al., 2009). The last have cautioned against the tyranny of technology, while a British curmudgeon with a 2002 Nobel Prize, Sydney Brenner, has reminded us that one person’s junk is another’s treasure—the real task being how to organize data so that they yield knowledge.

First, we must compliment Kotov et al. for accomplishing the daunting task of successfully following up their U.S. cohort with 10 years of data. True, Manfred Bleuler completed an exhaustive 23-year follow-up with a much more captive audience in the Burghölzli Hospital, in which he reported course changes both for better and worse even after 20 years for a majority of his cases (Bleuler, 1978). Thus, “outcome” cannot be equated with Bleuler’s “end state.” No clear distinction was seen in the Kotov study between the outcome of schizoaffective disorder and schizophrenia, indicating that the DSM-IV/-5 diagnostic differentiation is not valid. Instead, co-morbidity between affective disorder and schizophrenia in the nonhierarchical DSM classification system is proposed.

The co-appearance of affective disorder and schizophrenia has always been acknowledged. Papa Bleuler included attacks of mania or melancholia in his list of etiopathogenetic “primary symptoms” (not to be confused with his symptomatological “basic disturbances”; see Bleuler, 1911). Kraepelin mentioned that episodes of mania and depression were not uncommon in schizophrenic patients and that quite a number of patients presented with symptoms that did not allow a confident distinction between manic-depressive insanity and dementia praecox (Kraepelin, 1920). He proposed as a plausible explanation that the presentation of symptoms was determined by predisposing factors in the patients’ personalities for emotional or schizophrenic manifestation of the manic-depressive or schizophrenic illness.

Odegaard, unconstrained by either DSM or ICD, and using the national Norwegian psychiatric register which he had tirelessly constructed, observed the diagnostic distribution of probands and (only) their psychotic relatives (Odegaard, 1972). He routinely saw affective psychoses in the relatives of schizophrenics, and schizophrenic psychoses in the relatives of atypical affective psychoses plus manic-depressive psychoses. He favored some kind of a polygenic theory for his results (compare to Gottesman and Shields, 1967).

Having prominent affective symptoms or syndromes in patients with schizophrenia eventually was considered to be a schizoaffective subtype of schizophrenia, and since DSM-III/III-R and –IV and ICD-10, schizoaffective disorder has been differentiated as an independent category; in DSM it is nearer to schizophrenia than in ICD because DSM requires at least two weeks of non-affective psychosis. The separate classification has been supported by validating genetic studies (Bertelsen and Gottesman, 1995; Hamshere et al., 2009) and a major register-based cohort study, indicating that schizoaffective disorder is genetically linked to both mood disorder and schizophrenia as an intermediate form (Laursen et al., 2005).

In a recent Danish register-based study of schizophrenia and bipolar disorder in offspring of two, one, or no parent likewise affected (Gottesman et al., 2010), we observed a cumulative incidence of bipolar disorder in offspring of two schizophrenic parents that was 10 times higher than in the general population, and of schizophrenia in offspring of two parents with bipolar disorder four times higher than the population value. In children of one schizophrenic parent and the other with bipolar disorder, the incidence of schizophrenia and of bipolar disorder was two to three times the incidence from only one parent affected with either disorder. A major Swedish population-based study provided similar evidence that schizophrenia and bipolar disorder share a common genetic cause (Lichtenstein et al., 2009). In a sophisticated, eclectic discussion of the not yet disappearing dichotomy, Craddock and Owen conclude that a broadly defined schizoaffective illness “may be particularly useful for genetic studies” (Craddock and Owen, 2010), reprising their earlier empirical results with the WTCCC cohort (Hamshere et al., 2009).

In order to get nearer to the relation to the genetic predisposition than the present classification allows, it has been suggested to study domains of symptoms, (the NIMH Research Domains Criteria project [RDoC]; see Insel et al., 2010), particularly in endophenotype studies (Insel and Cuthbert, 2009; Gottesman and Gould, 2003) as a promising way of future research of the basic relationships among the disorders behind what we, for the time being, term schizophrenia, schizoaffective disorder, and bipolar disorder. The earlier Research Diagnostic Criteria (RDC) of Spitzer et al. (Spitzer et al., 1978) and the OPCRIT of McGuffin et al. (McGuffin et al., 1991) anticipated less constrained approaches to diagnosis that have shown their merit in genetically promising research. We find the conclusions of Hamshere et al. (Hamshere et al., 2009) compatible with our current understanding: "We hope that psychiatry is moving towards the time when our patients can benefit from diagnostic concepts that are built on solid foundations of empirical biological evidence rather than being perched precariously on the shifting sands of expert opinion."

References:

Kendler KS (2013) Psychosis Within vs. Outside of Major Mood Episodes: A Key Prognostic and Diagnostic Criterion. JAMA Psychiatry. Abstract

Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, Ziegler S, Cotsapas C, Sotoodehnia N, Glass I, Sunyaev SR, Kaul R, Stamatoyannopoulos JA. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012 Sep 7;337(6099):1190-5. Abstract

Cardno AG, Rijsdijk FV, West RM, Gottesman II, Craddock N, Murray RM, McGuffin P (2012) A twin study of schizoaffective-mania, schizoaffective-depression, and other psychotic syndromes. Am J Med Genet B Neuropsychiatr Genet. 159B(2):172-82. Abstract

Bertelsen A, Gottesman I I (1995) Schizoaffective Psychoses: Genetical Clues to Classification. American Journal of Medical Genetics (Neuropsychiatric Genetics) 60:7-11. Abstract

Laursen T M, Labourieau R, Licht R, Bertelsen A, Munk-Olsen T, Mortensen P B (2005) Family History of Psychiatric Illness as a Risk Factor for Schizoaffective Disorder. Arch Gen Psychiatry/vol 62: 841-848. Abstract

Gottesman I I, Laursen T M, Bertelsen A, Mortensen P B (2010) Severe Mental Disorders in Offspring with 2 Psychiatrically Ill Parents. Arch Gen Psychiatry vol 67(3): 252-257. Abstract

Lichtenstein P, Yip B H, Björk C, Pawitan Y, Cannon T D, Sullivan P F, Hultman C M (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373: 234-239. Abstract

Bleuler E (1911) Dementia præcox oder Gruppe der Schizophrenien. Deuticke Leipzig, Wien. English edition (1950) Dementia praecox or the group of schizophrenias. Intern. Univ. Press, New York.

Kraepelin E (1920) Die Erscheinungsformen des Irreseins. Z.f.d.g.Neur.u.Psych. LXII: 1-29.

Odegaard (1972) The multifactorial theory of inheritance in predisposition to schizophrenia. In: Kaplan, A.R., ed. Genetic Factors in "Schizophrenia." Springfield, III.: Charles C Thomas, Publisher, 1972. pp. 256-275.

Gottesman II, Shields J. (1967) A polygenic theory of schizophrenia. Proc Natl Acad Sci U S A. 1967 Jul;58(1):199-205. Abstract

Hamshere ML, Green EK, Jones IR, Jones L, Moskvina V, Kirov G, Grozeva D, Nikolov I, Vukcevic D, Caesar S, Gordon-Smith K, Fraser C, Russell E, Breen G, St Clair D, Collier DA, Young AH, Ferrier IN, Farmer A, McGuffin P; Wellcome Trust Case Control Consortium, Holmans PA, Owen MJ, O'Donovan MC, Craddock N. (2009) Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept. Br J Psychiatry. Jul;195(1):23-9. Abstract

Craddock N, Owen MJ. (2010) The Kraepelinian dichotomy—going, going... but still not gone. Br J Psychiatry; 196(2):92-5. Abstract

Insel T R, Cuthbert B, Garvey M et al. (2010) Research domain criteria (RDoC): Toward a new classification framework for research on mental disorders. Am J Psychiatry. 167: 748-751. Abstract

Insel T R, Cuthbert B N (2009) Commentary: Endophenotypes: Bridging Genomic Complexity and Disorder Heterogenity. Biol Psychiatry, 66: 988-989. Abstract

Gottesman I I, Gould T D (2003) The Endophenotype Concept in Psychiatry: Etymology and Strategic Intensions. Am J Psychiatry 160: 636-645). Abstract

Spitzer RL, Endicott J, Robins E. (1978) Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry; 35(6):773-82. Abstract

McGuffin P, Farmer A, Harvey I. (1991) A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Arch Gen Psychiatry; 48(8):764-70. Abstract

Bleuler, M. (1978) The schizophrenic disorders: Long-term patient and family studies. Yale University Press.

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Comments on Related News


Related News: Schizophrenia and Bipolar With Psychosis Share Cognition, Connectivity

Comment by:  Jose GoikoleaEduard Vieta
Submitted 18 July 2013
Posted 18 July 2013

The recent publication of two papers from the B-SNIP group in the American Journal of Psychiatry provides additional high-quality data supporting a dimensional model for psychotic disorders, different from the current Kraepelinian categorical model. These two papers focus on two different putative endophenotypes for schizophrenia and bipolar disorder, namely, cognitive performance and white matter integrity. Interestingly, both endophenotypes show quite similar results.

The work of the B-SNIP group is praiseworthy. Consisting of six centers across the United States, the group has studied quite a large sample of patients with psychotic disorders (schizophrenia, schizoaffective, and psychotic bipolar disorder) using both current categorical diagnostic criteria and a dimensional Schizo-Bipolar Scale approach. Besides that, the group assesses relatives without psychotic or affective disorders, which is essential for further understanding the underlying genetic basis and identifying endophenotypes for these disorders.

Both studies obtain similar results for each endophenotype: Both schizophrenia and bipolar disorder show abnormalities (in cognition and in white matter integrity) compared to healthy controls. There are no qualitative differences in these abnormalities; that is, they share a similar pattern of disturbance, although it is more severe (cognition) or widespread (white matter) in schizophrenia. These disturbances are shared to a lower degree by unaffected relatives, supporting their validity as endophenotypes, even if this is much clearer for relatives of schizophrenia subjects. Undoubtedly, these results support the notion of a single nosological entity with a dimensional nature. On the “schizophrenia edge” of the continuum, a more severe or widespread impairment as well as more abnormalities in unaffected relatives would be found.

However, there are some comments that should be taken into account for a fair interpretation of the results. First of all, the diagnosis of schizoaffective disorder has become somehow a test itself to validate the categorical versus dimensional model for psychotic disorders. The paper by Hill et al. compares the schizoaffective group with the healthy control group and with the other proband groups. The conclusions seem to support the dimensional model, as schizoaffective probands show an intermediate cognitive performance between schizophrenia and bipolar disorder without qualitative differences. Instead, for unclear reasons, the DTI paper splits the schizoaffective group in manic type merged with the bipolar group, and depressive type merged with the schizophrenia group, losing an opportunity to analyze this perspective.

Second, it is a shame that non-psychotic bipolar 1 patients have not been included in these studies. This represents a bias toward the psychotic view, whereas the inclusion of the non-psychotic bipolar subjects would have provided a second enriching view from the “affective” perspective. This second supplementary approach would be more likely to identify possible endophenotypic features that might differentiate schizophrenia from bipolar disorder. In fact, in light of these two papers, schizophrenia and bipolar disorder could be understood as the same disease, bipolar just being a less severe phenotype. Although there is quite large evidence that schizophrenia and bipolar disorder share different genetic, neurobiological, and cognitive features, and that a mixed categorical and dimensional approach may be much closer to reality, differences between both disorders should still be kept in mind. For instance, the unique clinical features of the most prototypical euphoric mania or the circadian rhythm disturbances in bipolar disorder are likely to be based on neurobiological features specific to bipolar disorder that are not yet completely understood or identified.

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Related News: Schizophrenia and Bipolar With Psychosis Share Cognition, Connectivity

Comment by:  Ole A. AndreassenMartin Tesli
Submitted 3 September 2013
Posted 4 September 2013

The two reports from the B-SNIP consortium elegantly address Kraepelin’s dichotomy in psychosis and provide evidence using a large sample that there are overlapping cognitive deficits across psychotic bipolar disorder and schizophrenia (Hill et al., 2013), and similar patterns of connectivity abnormalities (as measured by diffusion tensor imaging, or DTI) in the two disorders (Skudlarski et al., 2013). Both phenotypes are also found in relatives, supporting the idea that the cognitive and DTI measures are true "endophenotypes."

The finding that cognitive dysfunction in schizophrenia and psychotic bipolar disorder depends more on psychosis than a diagnostic group is a nice replication of our previous findings (Simonsen et al., 2011). This is reassuring and further suggests that it is a robust phenomenon, as the neuropsychological test batteries used in the two studies were quite different. The severity of the deficits is also comparable between the two studies.

The current study also investigated the familiality of cognitive dysfunction, which was quite high, with deficits also seen in non-psychotic relatives of both bipolar disorder and schizophrenia. Quite interestingly, the cognitive deficits were more associated with cluster A (psychosis-like) personality traits in relatives of bipolar disorder than in schizophrenia. This further strengthens the argument that there is a continuum of psychosis across these disorders which is heritable.

The paper by Skudlarski et al. reports brain imaging investigations (DTI) from the same sample. Decreased fractional anisotropy was found in multiple brain regions in schizophrenia and psychotic bipolar disorder subjects, and to a smaller extent in their relatives, than in healthy controls. These findings seem consistent, as 15 out of 18 regions have been previously reported in schizophrenia and 10 out of 21 in bipolar disorder. Further, the current results are in line with the continuum model of psychotic disorders and the polygenic architecture reported in recent mega-analyses (Lee et al., 2013).

Intriguingly, the authors found fractional anisotropy to be even better correlated with the "Schizo-Bipolar Scale" than with disease category. This proves the utility of cross-diagnostic clinical dimensions when investigating potential neurobiological mechanisms in psychiatric disorders. To bring this a step further, it would be interesting to know whether this clinical scale also correlates with fractional anisotropy (or neurocognition) within the bipolar disorder or the schizophrenia sub-sample separately.

In the perspective of the psychosis continuum model, it seems slightly contradictory that the investigators did not include schizoaffective disorder as a disease category on its own. Instead, they split this diagnostic group in two, classifying the depressed subgroup in the schizophrenia group and the manic subgroup in the psychotic bipolar disorder group. As a rationale for this classification, the authors reported controversial validity of the diagnostic status of schizoaffective disorder. If this controversy led to a split of the schizoaffective group in the paper by Skudlarski et al., why did the same controversy lead to the inclusion of schizoaffective disorder as its own category in the study by Hill et al.? Both approaches could potentially have been applied in both studies to actually explore this controversy in terms of neurocognition and white matter integrity.

Both studies support the hypothesis that reduced white matter integrity and impaired neurocognition are intermediate phenotypes in psychotic disorders. However, it might be debated whether these two features are causative in nature or merely correlate with the clinical symptomatology. Does reduced white matter integrity cause reduced neurocognition, which in turn gives rise to psychotic symptoms, or are the two latter phenomena independent but correlating effects of the former? Future studies should aim at disentangling these levels of correlating phenomena in biological psychiatric research. In line with this, it would be interesting to investigate the relationship between DTI measures and structural and functional MRI. Is the currently reported reduced white matter integrity reflected in the reductions identified with sMRI? And what consequences do these impairments have for brain activity as assessed with fMRI? Lastly, can these alterations be explained by genetic risk variants individually or in aggregate?

In summary, these two statistically well-powered studies have provided robust evidence for the continuum model in psychotic disorders. This is in accordance with findings from molecular genetics, brain imaging, and clinical studies. Now it is time to look for mechanisms behind these correlations.

References:

Hill SK, Reilly JL, Keefe RS, Gold JM, Bishop JR, Gershon ES, Tamminga CA, Pearlson GD, Keshavan MS, Sweeney JA. Neuropsychological Impairments in Schizophrenia and Psychotic Bipolar Disorder: Findings from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Study. Am J Psychiatry . 2013 Jun 17. Abstract

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Skudlarski P, Schretlen DJ, Thaker GK, Stevens MC, Keshavan MS, Sweeney JA, Tamminga CA, Clementz BA, O'Neil K, Pearlson GD. Diffusion tensor imaging white matter endophenotypes in patients with schizophrenia or psychotic bipolar disorder and their relatives. Am J Psychiatry . 2013 Aug 1 ; 170(8):886-98. Abstract

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