Is Schizoaffective Disorder a Useful Diagnosis?

Is Schizoaffective Disorder a Useful Diagnosis? Stephan Heckers, MD Corresponding author Stephan Heckers, MD Vanderbilt University Psychiatric Hospital, 1601 23rd Avenue South, Room 3060, Nashville, TN 37212, USA. E-mail: stephan.heckers@vanderbilt.edu Current Psychiatry Reports 2009, 11:332 337 Current Medicine Group LLC ISSN 1523-3812 Copyright 2009 by Current Medicine Group LLC A diagnosis of schizoaffective disorder is frequently used to describe a psychotic person with significant symptoms of depression and/or mania. The word schizoaffective was introduced by Jacob Kasanin in 1933 and has appeared in all editions of the DSM since 1952. However, the current DSM-IV-TR diagnosis of schizoaffective disorder is not reliable and is of limited clinical utility. The validity is built primarily on the prediction of course and outcome and on emerging findings from genetic and neurobiological studies. This review of the current status of schizoaffective disorder concludes with several suggestions for a revision of the diagnosis within a categorical or dimensional nosology of psychotic and affective disorders. Introduction Kasanin [1] introduced the term acute schizoaffective psychoses to describe nine patients who were initially diagnosed with dementia praecox but who achieved full recovery after several weeks of acute psychosis and affective symptoms. All editions of the DSM have included the term schizoaffective, but the diagnostic concept changed over time, especially with the introduction of diagnostic criteria in the DSM-III-R. Many clinicians and patients consider schizoaffective disorder to be an adequate diagnostic label for a person who is struggling with significant psychotic and affective symptoms. However, there are serious concerns about the reliability, clinical utility, and validity of the diagnosis. Should we continue or discontinue schizoaffective disorder as a diagnostic category? This review evaluates the current concept of schizoaffective disorder, explores recent literature, and proposes options for a revision of the diagnosis. Schizoaffective Disorder in the DSM-IV-TR There are four diagnostic criteria (A D) for the diagnosis schizoaffective disorder in the DSM-IV-TR (Table 1). Let us review how a clinician or researcher makes the diagnosis of schizoaffective disorder (after an organic etiology has been excluded, usually with a thorough physical and neurological examination, a review of the medical history, and a set of laboratory tests). First, the diagnosis will only be considered if a person has prominent psychotic and affective symptoms. The psychosis has to be severe enough to meet criterion A for schizophrenia, and the person needs to have significant affective symptoms during the same period of psychosis. This requires sufficient clinical data for a period of at least 1 month. This first step in the diagnostic process has thus far identified a person with an affective psychosis. Second, schizoaffective disorder needs to be distinguished from a primary mood disorder with psychotic symptoms. This is achieved via criterion B, which can be rephrased as follows: if a period of nonaffective psychosis lasting at least 2 weeks (during the same time period considered for criterion A) can be identified, then the diagnosis of a primary mood disorder can be excluded, and schizoaffective disorder should be considered. With criterion B, the DSM-IV-TR limits the diagnosis of schizoaffective disorder to the sequential type and provides a clear demarcation from severe psychotic bipolar disorder. In contrast, ICD-10 also recognizes the concurrent type of schizoaffective disorder [2]. Finally, the DSM definition of schizoaffective disorder goes one step beyond the exclusion of psychotic mood disorders. It also excludes cases that fulfill criteria A and B but do not have prominent mood symptoms. For example, a person with a 20-year history of schizophrenia and only two clear episodes of major depression will be excluded, as the mood symptoms did not occupy a substantial portion of the total illness duration. It is important to realize that the proper diagnosis of schizoaffective disorder requires access to longitudinal clinical data. This is different from many other DSM diagnoses, which are based on the evaluation of the hereand-now or brief periods of time (eg, 1 week for manic episode, 2 weeks for major depressive episode). Such longitudinal clinical data need to be assessed for temporal overlap (criterion B) and relative distribution over time

Is Schizoaffective Disorder a Useful Diagnosis? I Heckers I 333 Table 1. DSM-IV-TR criteria for schizoaffective disorder (abbreviated) A. An uninterrupted period of illness during which, at some time, there is either a major depressive episode, a manic episode, or a mixed episode concurrent with symptoms that meet criterion A for schizophrenia (ie, at least 2 of 5 symptoms [delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms], each present for a significant portion of time during a 1-mo period). B. During the same period of illness, there have been delusions or hallucinations for at least 2 wk in the absence of prominent mood symptoms. C. Symptoms that meet criteria for a mood episode are present for a substantial portion of the total duration of the active and residual periods of the illness. D. The disturbance is not due to the direct physiologic effects of a substance (eg, a drug of abuse, a medication) or a general medical condition. (criterion C). What does this mean for the diagnostic process? Most clinical and research settings do not allow for the direct observation of 4 or 6 weeks, but the diagnosis of schizoaffective disorder requires 1 month of data for criterion A and 2 weeks for criterion B. Therefore, most diagnoses of schizoaffective disorder must rely on accurate autobiographic memory of the patient, collateral information, or access to medical and mental health records. However, even if such data can be obtained and criteria A and B are met, it is difficult to accurately gauge the correct portion of illness with prominent mood symptoms. This is particularly challenging in patients who have suffered from a psychotic illness for many years. Finally, criterion C does not include a quantitative threshold and leaves it to the clinician to judge what constitutes a substantial portion of the illness duration. The History of Schizoaffective Disorder in the DSM The authors of the DSM have wrestled with the clinical challenge of accurately diagnosing patients with an affective psychosis. In the process, the diagnostic concept of schizoaffective disorder has evolved throughout the four editions and two revisions of the DSM. The DSM-I does not use the diagnosis of schizophrenia. Instead, it refers to schizophrenic reaction. One of the subtypes is schizophrenic reaction, schizoaffective type, about which the authors state the following [3]: This category is intended for those cases showing significant admixtures of schizophrenic and affective reactions. The mental content may be predominantly schizophrenic, with prolonged elation or depression. Cases may show predominantly affective changes with schizophrenic-like thinking or bizarre behavior On prolonged observation, such cases usually prove to be basically schizophrenic in nature. This sets the stage for the current concept of schizoaffective disorder as a schizophrenia-like illness. The DSM-II does use the diagnostic label schizophrenia and includes two subtypes: 1) schizophrenia, schizoaffective type, excited, and 2) schizophrenia, schizoaffective type, depressed. It holds on to the notion that this category is for patients showing a mixture of schizophrenic symptoms and pronounced elation or depression [4]. The DSM-III introduces the term schizoaffective disorder but does not propose any diagnostic criteria. The authors anticipate the still-ongoing debate about schizoaffective disorder [5]: Future research is needed to determine whether there is a need for this category and if so, how it should be defined and what its relationship is to schizophrenia and affective disorder. The category is retained in this manual without diagnostic criteria for those instances in which the clinician is unable to make a differential diagnosis with any degree of certainty between affective disorder and either schizophreniform disorder or schizophrenia. It appears that the first three editions of the DSM simply addressed the clinical need to provide a diagnostic term for patients who did not fit into either schizophrenia or bipolar disorder. The DSM-III-R operationalized for the first time the diagnostic criteria and separated two subtypes: bipolar and depressive type. The manual captures the history and diagnostic challenges well [6]: The term schizoaffective disorder has been used in many different ways since it was first introduced as a subtype of schizophrenia, and represents one of the most confusing and controversial concepts in psychiatric nosology. The approach taken in this manual emphasizes the temporal relationship of schizophrenic and mood symptoms. As noted above, this defines the sequential subtype of schizoaffective disorder. The authors offer the following justification for the inclusion of the diagnosis and the definition of criteria: this description of schizoaffective disorder appears to have tentative validity from prognostic, treatment, and family studies as delimiting an entity [6]. The three validators mentioned are a chronic course, a prognosis that is somewhat better than schizophrenia, and a familial pattern of increased risk

334 Schizophrenia and Related Psychotic Disorders I of schizophrenia in first-degree biologic relatives with [schizoaffective disorder]. The DSM-IV introduced the current text to define schizoaffective disorder (Table 1) and included a mixed form of the bipolar subtype but did not change the diagnostic criteria established in the DSM-III-R [7]. There were no further changes in the DSM-IV-TR [8]. Despite listing the somewhat better prognosis of schizoaffective disorder in the DSM-III-R as a potential validator, the DSM never embraced Kasanin s notion of schizoaffective disorder. Clinical features such as phasic course, interepisode recovery, and good outcome were not included as diagnostic criteria. Kasanin s concept of schizoaffective seems to be more in line with bouffée délirante, a French diagnosis of the 19th century, and the current ICD diagnosis of acute and transient psychotic disorder. In summary, the authors of the DSM always acknowledged that the borderland of psychotic and affective disorders is more complex than the simple dichotomy of schizophrenia and mood disorder makes us believe, but how does the schizoaffective disorder diagnosis address this complexity? Reliability and Clinical Utility Reliability and clinical utility are conditiones sine qua non for the validity and ultimate value of a diagnosis [9 ]. First, any psychiatric diagnosis is noisy and subject to potential error. It would be ideal if a patient always received the same diagnosis (by the same rater over time and by different raters at the same time), but this is usually not the case. Therefore, a diagnostic criterion that minimizes noise in the diagnostic process and increases intra- and interrater reliability is of great value. The introduction of operationalized criteria in the DSM-III-R and the subsequent increase in reliability are generally considered to be major achievements in recent psychiatric nosology. Second, criteria need to be practical. A criterion may ensure a highly reliable diagnosis, but it is of limited clinical utility if the necessary clinical information is difficult to obtain. For example, if longitudinal data need to be collected, then the reliability of the diagnosis will depend more on the consistent availability of information over time rather than the reliability of the diagnostic procedure at one point in time. The DSM-IV field trials provided promising data on the reliability of the criteria for schizoaffective disorder. A total of 165 patients were studied at different sites, and the interrater (0.48 0.66) and test retest (0.48 0.56) reliability were deemed to be in the fair to good range [10]. These estimates are at odds with several reports in the literature that have seriously challenged the reliability and clinical utility of the diagnosis of schizoaffective disorder. Nurnberger et al. [11] reported excellent reliabilities for several psychiatric disorders using the algorithms of the Diagnostic Interview for Genetic Studies, except in the case of schizoaffective disorder, for which disagreement on estimates of duration of mood syndromes relative to psychosis reduced reliability. This led to an explicit threshold in the third edition of the Diagnostic Interview for Genetic Studies: mood symptoms needed to be present for at least 30% of the total duration of psychosis to make the diagnosis of schizoaffective disorder. Maj et al. [12] reported low reliability scores for criteria A, B, and C for schizoaffective disorder, with the lowest being 0.29 (Cohen s!) for criterion C. The temporal stability of the schizoaffective disorder diagnosis is low. Schwartz et al. [13] reported 6- and 24- month follow-up assessments after an initial assessment at first admission to a psychiatric inpatient facility and found that the diagnoses were stable in 92% of cases for schizophrenia, 83% for bipolar disorder, and 74% for major depression, but only 36% for schizoaffective disorder. Salvatore et al. [14 ] observed 500 first-episode psychotic disorder patients for 2 years and reported a change in the categorical diagnoses in 22.4% of all cases. The major change was an increase in the schizoaffective disorder diagnosis from 0.2% to 12.2% of all cases, primarily due to the emergence of newly perceived affective features among those initially diagnosed with a nonaffective psychosis. Finally, the clinical utility has been questioned. When 59 patients with a discharge diagnosis of schizoaffective disorder given by a clinician were re-evaluated by a research team, none of them were found to meet the DSM-IV criteria [15]. Taken together, the sequential nature (criterion B) and the estimation of the duration of mood symptoms over the entire duration of the illness (criterion C) make the DSM-IV-TR definition of schizoaffective disorder a challenge even for the most skilled diagnostician. Validity The history of the diagnosis of schizoaffective disorder illustrates the different concepts of validity of a psychiatric diagnosis [16,17,18,19 ]. Here I focus on two aspects: course/outcome and genetic/neural mechanisms. Course and outcome Patients diagnosed with schizoaffective disorder tend to have a better outcome than patients diagnosed with schizophrenia [20] and a worse outcome compared with those diagnosed with bipolar disorder [21]. A longitudinal 15-year follow-up of schizoaffective disorder patients revealed that at the time of first hospitalization, schizoaffective disorders were distinguishable from both schizophrenia and affective disorders, but long-term outcome of schizoaffective disorder was similar to that of affective disorders [22]. However, course and outcome are not diagnostic criteria for schizoaffective disorder in the DSM. This could explain some of the appeal of schizoaffective disorder in clinical practice, as it avoids a

Is Schizoaffective Disorder a Useful Diagnosis? I Heckers I 335 prediction of poor outcome and the bias associated with it. This implicit poor-to-good outcome gradient in the DSM (schizophrenia > schizoaffective disorder > affective disorder) is in contrast to the diagnostic system developed by Leonhard [23], which makes explicit and strong outcome predictions for affective psychoses. Genetic and neural mechanisms Studies of probands with schizophrenia have revealed an increased risk for schizoaffective disorder in fi rstdegree relatives [19 ]. At the same time, studies of probands with schizoaffective disorder have revealed an increased risk for schizophrenia, bipolar disorder, and schizoaffective disorder [24]. This has led some to conclude that schizoaffective disorder is not simply a subgroup of bipolar disorder or schizophrenia but rather a genetic intermediate form. There is now increasing evidence for shared genetic mechanisms of schizophrenia and bipolar disorder. This includes linkage to loci on chromosomes 1q42, 6q22, 8p21, 9q31, 13q32, and 15q14 and the identification of positional candidate genes G72/G30, NRG1, and DISC1, conferring an increased risk for both disorders [19 ]. Genome-wide linkage scans in patients with the diagnosis of schizoaffective disorder have reported signals at 1q42, 22q11, and 19p13 [25]. This has been interpreted as evidence that some susceptibility genes have specificity to schizophrenia, others to bipolar disorder, and that some confer risk across the spectrum. A growing number of studies have identified similarities and differences between schizophrenia and bipolar disorder with regard to brain structure, brain function, and cognition. Many of these studies have included schizoaffective disorder diagnoses, often grouped together with schizophrenia. Convergent findings include structural abnormalities of the cerebral cortex [26], abnormal function of "-aminobutyric acid positive interneurons [27], and impaired cognition [28]. With all this taken together, the diagnosis of schizoaffective disorder has frequent clinical usage as an intermediate between schizophrenia and affective disorder without compelling validation by outcome, genetic, or neuroscientific studies. Where can we go from here? Before we explore options for the DSM-V, we need to review how the diagnosis fits into the current nosology of psychotic disorders. The Major Theoretical Models of Psychosis Schizoaffective disorder is the result of the Kraepelinian dementia praecox/manic depressive illness dichotomy. According to Kraepelin [29], the two diagnoses are validated by outcome (poor vs good), clinical picture (deficits of volition, cognition, and affect vs depressive and/or manic episodes with interepisode recovery), and pathology (cortical lesion vs unknown or no lesion). However, many clinicians have found it difficult to assign a significant number of patients to either schizophrenia or one of the two major mood disorders. After his retirement, even Kraepelin [30] himself expressed doubts about whether patients with an affective psychosis could be grouped accurately into either schizophrenia or manic depressive illness. Over the years, there have been three approaches to addressing this nosological challenge. First, psychotic and affective disorders are dichotomous categories. This includes Kraepelin s original strong position and many variants, giving rise to subtypes such as schizoaffective disorder and deficit/nondeficit schizophrenia [31] and even more detailed groupings derived from latent-class analysis [32]. Second, psychotic and affective disorders are a continuum. This unitary psychosis model predates Kraepelin and continues to attract interest today. Proponents of this model argue that 1) there is no point of rarity to distinguish psychotic from affective patients and 2) there are no clear validators such as outcome or disease mechanism. Therefore, dimensions (eg, hallucination, delusion, avolition, depression, and mania) should be used to characterize patients, not categorical distinctions. Third, there is neither a dichotomy nor a continuum. Psychotic and affective symptoms can occur in the same patient and in various constellations. Diagnoses are then built upon psychopathology and outcome [23] or on mechanism and treatment response [33]. Within these three nosologies of psychosis, there are several possible definitions of schizoaffective disorder: 1. Distinct diagnostic entity (the DSM-IV-TR concept) 2. Variant of schizophrenia or mood disorder 3. Heterogeneous group (some are patients with schizophrenia, some are patients with a mood disorder) 4. Form of concurrent schizophrenia and mood disorder 5. On a continuum between schizophrenia and mood disorder. Options for the DSM-V Considering the current status of the schizoaffective disorder diagnosis and the major nosological positions, there are at least five options for the DSM-V, each increasingly more radical (Table 2). Making no changes is not reasonable because the evidence reviewed here overwhelmingly favors a change. At a minimum, criterion C must be revised simply because of poor reliability and questionable feasibility. Reliability could be increased by including a quantitative threshold (eg, 30%), but the significant challenge of collecting data for such an assessment would remain. In addition, criterion B should be reviewed, as it excludes the concurrent subtype of schizoaffective disorder (which is included in the ICD definition of schizoaffective disorder). As a next step, the diagnosis of schizoaffective disorder could be removed, leaving schizophrenia, bipolar

336 Schizophrenia and Related Psychotic Disorders I Table 2. Options for the diagnosis of schizoaffective disorder in the DSM-V 1. No change 2. Revise the diagnostic criteria Specify an explicit threshold for criterion C Include concurrent subtype of schizoaffective disorder (ie, remove criterion B) 3. Continue with schizophrenia, bipolar disorder, and major depression but remove schizoaffective disorder Add specifier criteria to the diagnostic criteria of schizophrenia, bipolar disorder, and major depression Categorical specifiers Dimensional specifiers Add no specifier criteria 4. Discontinue psychotic disorder categories and define 1 psychosis spectrum 5. Discontinue all diagnostic categories and define dimensions to capture psychopathology disorder, and major depression in place. Affective psychosis could then be described with specifier criteria (using categories or ordinal rating scales) that would be added to these three diagnoses. This would create three mixed categories (schizophrenia + affective symptoms, bipolar disorder + psychotic symptoms, and major depression + psychotic symptoms) and would in part resemble the first two editions of the DSM, which defined schizoaffective disorder as a subtype of schizophrenia. Removing schizoaffective disorder without adding specifiers would not be an improvement because it would ignore the substantial clinical overlap between psychotic and mood disorders. Only a radical change of the current nosology would result in the removal of the diagnosis of schizophrenia (or all diagnostic categories). Such a change would make schizoaffective disorder obsolete. A dimensional diagnostic system would then be required to capture affective psychosis with multiple dimensions. Conclusions The fifth edition of the DSM provides the opportunity to improve the reliability and clinical utility of the schizoaffective disorder diagnosis. Based on the available evidence, we need to revise the current criteria, which have been unchanged since 1987. However, current scientific data are not yet sufficient to definitively decide the nosology of affective psychosis. Acknowledgment Dr. Heckers is a member of the DSM-V Work Group on Psychotic Disorders. The opinions expressed in this article do not necessarily reflect the consensus of the DSM-V Work Group or Task Force. Disclosure No potential conflict of interest relevant to this article was reported. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Kasanin J: The acute schizoaffective psychoses. Am J Psychiatry 1933, 90:97 126. 2. Marneros A: The schizoaffective phenomenon: the state of the art. Acta Psychiatr Scand Suppl 2003, 418:29 33. 3. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, edn 1. Washington, DC: American Psychiatric Association; 1952. 4. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, edn 2. Washington, DC: American Psychiatric Association; 1968. 5. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, edn 3. Washington, DC: American Psychiatric Association; 1980. 6. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, edn 3 (revised). Washington, DC: American Psychiatric Association; 1987. 7. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, edn 4. Washington, DC: American Psychiatric Association; 1994. 8. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, edn 4 (text revision). Washington, DC: American Psychiatric Association; 2000. 9. Kraemer HC: DSM categories and dimensions in clinical and research contexts. Int J Methods Psychiatr Res 2007, 16(Suppl 1):S8 S15. This article reviews the theoretical advantages of a dimensional assessment of psychiatric patients over the current categorical assessment in the DSM-IV-TR. It proposes adding categorical diagnoses in the DSM-V. 10. Flaum M, Amador X, Gorman JM, et al.: DSM-IV field trial for schizophrenia and other psychotic disorders. In DSM-IV Sourcebook. Edited by Widiger TA, Frances AJ, Pincus HA, et al. Washington, DC: American Psychiatric Association; 1994:687 713. 11. Nurnberger JI Jr, Blehar MC, Kaufmann CA, et al.: Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 1994, 51:849 859; discussion 863 864. 12. Maj M, Pirozzi R, Formicola AM, et al.: Reliability and validity of the DSM-IV diagnostic category of schizoaffective disorder: preliminary data. J Affect Disord 2000, 57:95 98. 13. Schwartz JE, Fennig S, Tanenberg-Karant M, et al.: Congruence of diagnoses 2 years after a first-admission diagnosis of psychosis. Arch Gen Psychiatry 2000, 57:593 600.

Is Schizoaffective Disorder a Useful Diagnosis? I Heckers I 337 14. Salvatore P, Baldessarini RJ, Tohen M, et al.: McLean-Harvard International First-Episode Project: two-year stability of DSM-IV diagnoses in 500 first-episode psychotic disorder patients. J Clin Psychiatry 2009, 70:458 466. The authors of this study observed fi rst-episode patients over a 2-year period and documented a high conversion rate of schizophrenia to schizoaffective disorder, as mood symptoms were not prominent during the initial evaluation but evolved during the study period. 15. Vollmer-Larsen A, Jacobsen TB, Hemmingsen R, Parnas J: Schizoaffective disorder the reliability of its clinical diagnostic use. Acta Psychiatr Scand 2006, 113:402 407. 16. Abrams DJ, Rojas DC, Arciniegas DB: Is schizoaffective disorder a distinct categorical diagnosis? A critical review of the literature. Neuropsychiatr Dis Treat 2008, 4:1089 1109. 17. Cheniaux E, Landeira-Fernandez J, Lessa Telles L, et al.: Does schizoaffective disorder really exist? A systematic review of the studies that compared schizoaffective disorder with schizophrenia or mood disorders. J Affect Disord 2008, 106:209 217. This was a comprehensive review of the evidence for and against the diagnosis of schizoaffective disorder as an independent class between schizophrenia and mood disorders. 18. Malhi GS, Green M, Fagiolini A, et al.: Schizoaffective disorder: diagnostic issues and future recommendations. Bipolar Disord 2008, 10:215 230. 19. Potash JB: Carving chaos: genetics and the classification of mood and psychotic syndromes. Harv Rev Psychiatry 2006, 14:47 63. This was a thoughtful analysis of the nosology of affective psychosis combined with a review of the genetic epidemiology and molecular genetics. 20. Harrow M, Grossman LS, Herbener ES, Davies EW: Ten-year outcome: patients with schizoaffective disorders, schizophrenia, affective disorders and mood-incongruent psychotic symptoms. Br J Psychiatry 2000, 177:421 426. 21. Strakowski SM, Keck PE Jr, Sax KW, et al.: Twelve-month outcome of patients with DSM-III-R schizoaffective disorder: comparisons to matched patients with bipolar disorder. Schizophr Res 1999, 35:167 174. 22. Jager M, Bottlender R, Strauss A, Moller HJ: Fifteen-year follow-up of ICD-10 schizoaffective disorders compared with schizophrenia and affective disorders. Acta Psychiatr Scand 2004, 109:30 37. 23. Leonhard K: Aufteilung der Endogenen Psychosen. Berlin: Akademie Verlag; 1957. 24. Laursen TM, Labouriau R, Licht RW, et al.: Family history of psychiatric illness as a risk factor for schizoaffective disorder: a Danish register-based cohort study. Arch Gen Psychiatry 2005, 62:841 848. 25. Hamshere ML, Bennett P, Williams N, et al.: Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13. Arch Gen Psychiatry 2005, 62:1081 1088. 26. Murray RM, Sham P, Van Os J, et al.: A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophr Res 2004, 71:405 416. 27. Benes FM, Berretta S: GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001, 25:1 27. 28. Hill SK, Harris MS, Herbener ES, et al.: Neurocognitive allied phenotypes for schizophrenia and bipolar disorder. Schizophr Bull 2008, 34:743 759. 29. Kraepelin E: Psychiatrie. Ein Lehrbuch für Studierende und Ärzte. Achte, Vollständig Umgearbeitete Auflage. 3. Band. Klinische Psychiatrie. 2. Teil. Leipzig, Germany: Verlag Von Johann Ambrosius Barth; 1913. 30. Kraepelin E: Die erscheinungsformen des irreseins. Z Gesamte Neurol Psychiatr 1920, 62:1 29. 31. Carpenter WT Jr, Buchanan RW, Kirkpatrick B, et al.: Strong inference, theory testing, and the neuroanatomy of schizophrenia. Arch Gen Psychiatry 1993, 50:825 831. 32. Kendler KS, Karkowski LM, Walsh D: The structure of psychosis: latent class analysis of probands from the Roscommon Family Study. Arch Gen Psychiatry 1998, 55:492 499. 33. Fink M, Taylor MA: The medical evidence-based model for psychiatric syndromes: return to a classical paradigm. Acta Psychiatr Scand 2008, 117:81 84.