Schizophrenia Research Forum - A Catalyst for Creative Thinking

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 Dec 1 ; 70(12):1276-86. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Irving Gottesman, SRF AdvisorAksel 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."


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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