Competing Definitions of Schizophrenia: What Can Be Learned From Polydiagnostic Studies?

Abstract

The contemporary diagnoses of schizophrenia (sz)—Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition(DSM-IV) and International Classification of Diseases,10th Revision(ICD-10)—are widely considered as important scientific achievements. However, these algorithms were not a product of explicit conceptual analyses and empirical studies but defined through consensus with the purpose of improving reliability. The validity status of current definitions and of their predecessors remains unclear. The so-called “polydiagnostic approach” applies different definitions of a disorder to the same patient sample in order to compare these definitions on potential validity indicators.

We reviewed 92 polydiagnostic sz studies published since the early 1970s. Different sz definitions show a considerable variation concerning frequency, concordance, reliability, outcome, and other validity measures. The DSM-IV and the ICD-10 show moderate reliability but both definitions appear weak in terms of concurrent validity, eg, with respect to an aggregation of a priori important features. The first-rank symptoms of Schneider are not associated with family history of sz or with prediction of poor outcome. The introduction of long duration criteria and exclusion of affective syndromes tend to restrict the diagnosis to chronic stable patients. Patients fulfilling the majority of definitions (core sz patients) do not seem to constitute a strongly valid subgroup but rather a severely ill subgroup. Paradoxically, it seems that a century after the introduction of the sz concept, research is still badly needed, concerning conceptual and construct validity of sz, its essential psychopathological features, and phenotypic boundaries.

Introduction

Schizophrenia (sz) remains an elusive entity, and the history of psychiatric research is replete with the attempts at formalizing its definition and hence to distinguish it from other disorders as well as the attempts at various internal subdivisions (eg, acute—chronic or poor premorbid—good premorbid subtypes). In fact, since the introduction of the concept, psychiatry has produced not less than 40 definitions of sz.

These historical permutations naturally sink gradually into oblivion with the most recent algorithms (such as Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] and International Classification of Diseases, 10th Revision [ICD-10]) acquiring the aura of important epistemological achievements with solid empirical foundations and insidiously reified into truly existing natural entities.^{1, 2} Yet, it is important to realize that the operational diagnoses of today owe their shape not so much to their scientific foundations but to pragmatic needs and ensuing decisions to increase international consensus.

One possible investigative approach to the reliability and validity of sz definitions is to compare these definitions between themselves and with their historical predecessors. For example, to say that ICD-10 is superior to ICD-8/ICD-9 requires comparing these 2 algorithms with respect to some validating data of interest. The purpose of this study is to provide a review of such a polydiagnostic approach in sz research. This goal gains in urgency, given the ongoing contemplation of yet another change in the diagnostic systems.

The polydiagnostic approach^3–5 consists of applying different sets of criteria for a given diagnostic category to the same group of patients in order to assess the degree of concordance between the diagnoses and/or to compare their validity indicators.

Materials and Method

The Medline searches were performed for all clinical and epidemiological studies published since 1970 comparing at least 2 definitions of sz. The Medline search was supplemented by screening references of the individual articles. Studies that did not indicate the numbers of patients with a given diagnosis were not included.

A preestablished scheme was used to record which and how many definitions were used, number of patients, the inclusion criteria, rating setting, the interrater reliability, the diagnostic concordance, follow-up assessments and their results, and other types of validation. Because the studies and hence the data were too heterogeneous, it was not possible to perform a systematic review, where the individual studies could enter into a meta-analytic approach.

Results

We have identified more than 100 articles published between 1972 and 2005, referring to 92 polydiagnostic studies. Twenty-six of these were follow-up studies. An overview of all studies appears in table 1.

Table 1.

The Polydiagnostic Studies

First author and year of publication	No. of Definitions of Schizophrenia (abbreviations of diagnostic definitionsa)	Sample (No. of patients included; diagnostic groups; design: follow-up [period: mean and/or range of years; no. {or %} of patients followed up]	Diagnostic Frequencies (%) (by all/by at least one definition; (range); concordance: mean, (range)	Validity (outcome: H = hospitalization, P = psychopathology, S = social function)
Shields 197260	6 raters (clinical diagnoses)	57 twin pairs (24 MZ, 33 DZ); index twin: schizophrenia	-/-; (38–68); Mean: 79.4%	Twin concordance: highest in broadest criteria but best MZ:DZ discrimination with “middle-of-the-road” criteria
WHO-IPSS 1973,36 1979104	3 (ICD8, McKeon, Catego)	1202; Patients with functional psychosis of recent onset; multicenter design; follow-up (2 y; 75.5%)	25/-; (46–67); κb: ICD8/Catego: 0.68, ICD8/McKeon: 0.25	Psychopathology: concordant patients more often males, single, no precipitating factors, hallucinations, delusions, flatness of affect, less depressed, higher cross-centee stability
Strauss1974105	3 (DSM2, FRS, Langfeldt)	142; Psychotic inpatients; follow-up (2 y, N = 111)	-/-; Follow-up: (26–77); —	Outcome (H, P, S): no significant differences
Hawk 1975106	3 (DSM2, FRS, Langfeldt)	131; Psychotic inpatients; follow-up (5 y, N = 80)	Follow-up patients: 76/76; (24–76); —	Outcome (H, P, S): no significant differences between different groups of schizophrenics
Taylor 1975107	2 (Feig, Taylor)	111; First-admission psychosis (clinical diagnosis of schizophrenia: N = 89)	The 89 patients: 6/18; (11–12); κ = –0.27	Differentiation by the single criteria of Feig: no major differences between clinical schizophrenia and mania
Newmark 1976108	4 (Bleu, FRS, Newmark, Yusin)	335; Inpatients (DSM2 schizophrenia: N = 108)	-/-; (21–47); Significant differences	Correspondence with DSM2 diagnosis: Bleu lowest correspondence
Strauss 197719	8 (DSM2, Feig, Flex, FRS, NHSI, RDC)	272; First-admission, functional psychiatric disorder	-/45; (1–25); —	—
Brockington (Camberwell sample) 197813	9; (Catego, Feig, Flex6, Forrest, FRS, Langfeldt, NHSI, Taylor)	119; First admission, possibly functional psychosis	25/-; At least 1 of 4 definitions: 53; (3–38); κ = 0.29; (0.04–0.67)	—
Brockington (Netherne sample) 197813 Kendell 197945	7 (Catego, Flex, FRS, Langfeldt, NHSI, RDC)	134; Inpatients with ICD8 functional psychosis; follow-up (6.5 y, N = 118)	Outcome diagnoses: 10/-; At least 1 of 6 definitions: 63; (18–36); κ = 0.59; (0.37–0.79)	Outcome (H, P, S): Prediction of symptomatic outcome more successful than of social outcome
Koehler 1978109	2 (Feig, Taylor)	116; First-admitted patients with schizophrenia without FRS	18/31; (20–29); Feig vs Taylor: κ = 0.52	—
Overall 197941	6 sets of research diagnostic criteria (CDC, Feig, Flex, RDC, SI, TAC)	166; Schizophrenia patients	-/-; (27–92); Disagreement	Agreement with clinical diagnosis of schizophrenia: 27–92%. No definition superior to another
Bland 1979,42 1980110	3; (Feig, FRS, NHSI)	43; First-admission schizophrenia; follow-up (14 y, N = all)	-/-; (88–98); —	Outcome (P, S): related to Feig, not to FRS
Stephens 198046	7 (Bland, DSM2, Feig, Flex, FRS, NHSI, RDC)	120; Predominantly schizophrenia patients; follow-up (9.8 y, N = 82)	-/-; (39–89); RDC vs all except DSM2: κb (0.24–0.37)	Outcome (H, P, S): not predicted by FRS (among others)
Helzer 198147	4 (Catego [broad], DSM3, Feig, RDC)	134; Inpatients with functional psychosis (= Brockington's Netherne sample 1978); follow-up (6.5 y [5–8.3]; N = 125)	Outcome diagnoses: -/-; (14–42); κ (0.24–0.84)	Outcome (H, P, S): DSM3 and Feig identified poor outcome patients
Singerman 198143	3 (DSM3, Feig, RDC)	216; Psychiatric patients and nonpatients	-/-; (12–19); κ (0.38–0.59)	—
Berner 19823	8 (Bleu, Feig, FRS, RDC, VRC—no raw data on: Catego, ICD9, Taylor)	100; Functional psychosis	-/-; 5 Definitions: (21–59); 33–86%	—
Endicott 1982111	10 (DSM3, Feig, Flex, NHSI, RDC, Taylor)	168; Inpatients	1/27; (4–26); Dramatic differences	—
Stephens 198231	9 (Astrup, DSM1, DSM3, Feig, Flex, FRS, NHSI, RDC, Taylor)	283; Psychotic inpatients; follow-up (5–16 y, N = all)	7/97; (37–88); κ (0–0.69)	Outcome (P, H): predicted by DSM3 but not FRS
Klein 198232	7 (DSM3, Feig,c Flex, FRS, RDC, Taylor)	46; Patients with DSM2 and NHSI schizophrenia	7/87; (24–63); κ (–21– 0.84)	Premorbid adjustment and chronicity (retrospective): FRS had better premorbid adjustment
Asnis 198265	6 (Flex, Feig, NHSI, RDC, Taylor)	47; Chronic, hospitalized patients with RDC schizophrenia	64/100; (64–100); 4 Definitions: κb (0.08–0.47)	Outcome (H, P, S): better prognosis for non-Taylor; Family history of schizophrenia spectrum disorders: no significant differences
Silverstein 198221	3 (DSM2, DSM3, RDC)	252; Inpatients	-/-; (24–41); —	—
Young 1982112	4 (Flex, FRS, RDC, Taylor)	196; Inpatients (not only mild symptoms)	5/52; (19–30); Significant agreement	Latent class analysis: blunted affect and absence of affective syndromes related to latent class schizophrenia
Helmes 198311	13 (Bleu, DSM3, Edwards, Feig, Flex, Kraep, Langfeldt, MBleu, Newmark, Willis, Yusin)	31; Outpatients with chronic schizophrenia (a subsample of Cernovsky 1985); retrospective design (10.8 y, N = all)	-/-; (Flex 80, Feig 91); —	—
Schanda 198449	5 (DSM3, FRS, ICD9, RDC, VRC)	90; Patients with delusional syndromes; follow-up (6–9 y, N = 84)	-/-; (8–51); —	Outcome (course prognosis: episodic or chronic; P): DSM3, ICD9, and RDC: more chronic course. Affective symptomatology: high prognostic value
McGlashan 198444	4 (DSM3, Feig, NHSI, RDC)	400; residentially treated inpatients; follow-up (2–15 y, N = 330)	-/-; (28–55); vs “established use”: κ (0.49–0.56)	Diagnostic stability: Feig most stable. Outcome (P, S): all definitions had predictive validity; Feig had the poorest outcome
McGuffin 198462	6 (Feig, Flex, FRS, RDC, Taylor, Tsuang + diagnostician judgments)	60 twin pairs: 26 MZ, 34 DZ; index twin probands schizophrenic	-/-; (13–45); —	Probandwise concordance: MZ concordance 11–58% (lowest Flex(6), highest Tsuang hebephrenic). MZ correlation in liability: 0.59–0.93. Estimated morbid risk: 0.19–0.65%.
Westermeyer 198451	2 (DSM2, DSM3)	153; Patients with DSM2 schizophrenia (43% first admission); follow-up (median 2.3 y, N = all)	41/100; (41–100); —	Outcome (H, P, S): sex the most powerful predictor of overall outcome in DSM2, but not in DSM3
Lewine 1984,20 Burbach 1984113	6 (Feig, Flex, FRS, NHSI, Taylor, RDC)	387; Inpatients; patients with only mild symptoms excluded	-/-; (2–60); κ = 0.24; (0.02–0.47)	Sex ratio: more stringently defined schizophrenia yielded a significantly greater male to female ratio
Rosen 1984114	4 (Flex, FRS, Langfeldt, RDC)	46; Drug-free male inpatients with RDC or Feig schizophrenia	-/100; (74–100) Flex not included; —	Presence of positive and negative symptoms: positive correlation within RDC paranoid and undifferentiated subtypes
Kendler 1984,24 Gruenberg 1985100	4 (DSM3, ICD9, RDC, Tsuang)	187; Inpatients with Feig schizophrenic; follow-up (short-term: 2.5 y, N = 172; long-term: 24 y, N = 175)	100/100; 100; Subtypes: κ (0.21–1.00)	Outcome (H, P, S): paranoid subtype best outcome; Tsuang more successful at predicting outcome
Cernovsky 1985,28 Landmark 1986,29 1990,30 Helmes 2003115	13 (Bleu, DSM3, Edwards, Feig, Flex, FRS, Kraep, Langfeldt, Mbleu, Newmark, Willis, Yusin)	120; Schizophrenia outpatients on depot injections; Helmes: a subgroup of 107 patients with schizophrenia by most systems	24/100; (35–93); Phi (0.08–0.72)	Intercorrelation with social and anamnestic variables: Kraep correlated with social adjustment; Feig longer prodrome. Correspondence of a symptom “triad” with the other definitions (phi): 0.24–0.64; Helmes: Cluster analysis of symptoms: no unambiguous solution for no. of clusters, limited support for historical subtypes
Kulhara 198635	6 (Catego, DSM3, Feig, FRS, ICD9, RDC)	112; patients with ICD9 schizophrenia	17/100; (43–100); All except ICD9: κ (0–0.64)	Subtypes: 15 of 17 patients meeting all criteria had paranoid schizophrenia
Ben-Tovim 198675	2 (DSM3, ICD9)	Villages in Botswana (N = 2625); demographic design	-/-; —; —	1-y prevalence (age adjusted): DSM3 43 and ICD9 53 per 10 000
Berner 1984,77 1986,26 Lenz 1986,27 1991,116 Katschnig 198876	8 (Bleu and FRS vs DSM3, Feig, ICD9, RDC, Taylor, VRC)	200; First-admission patients with ICD9 functional psychosis; follow-up (7 y, N = 186)	-/-; (21–61); —	Sex ratio and age of onset: More males and earlier onset in narrow definitions. Male patients lower age of onset; Probability of diagnosis: Bleu symptoms considered more significant than FRS symptoms for schizophrenia by all systems. Duration of hospital stay: correlated with formal thought disorder; Diagnostic stability of ICD9, RDC, and DSM3
Coryell 1987117	3 (DSM3, Feig, RDC)	98; Inpatients with nonmanic psychoses; follow-up (0.5 y, N = all)	-/-; (20–37); 53–86%	Outcome (P, S): family history of major depression: DSM3 not different from affective patients
Cooper 198766	2 (DSM3, ICD9)	Patients with broad ICD9 schizophrenia in a catchment area; demographic design	-/-; —; —	Annual incidence rates (by sex and age): 8–20 per 100 000. Male-to-female ratio: 2.2–2.4
Tandon 1987118	2 (FRS, RDC)	294; Inpatients	12/25; (19–20); κb = 0.47	Predictive value of FRS: 90%. Specificity of FRS for schizophrenia vs major depression = 97%
Jorgensen 1987119	2 (DSM3, ICD8)	129; Mothers with a clinical diagnosis of schizophrenia (The Copenhagen High-risk Study)	81/94; (84–91); κb = 0.42	—
Modestin 198750	5 (Bleu, DSM3, Flex, FRS, RDC)	52; Schizophrenia patients admitted with acute psychotic decompensation	-/100; (22–77); κb (–0.07–0.34)	Presence of basic symptoms (FCQ): no significant differences
Levav 198769	3 (DSM3, NHSI, RDC)	509; First admissions	-/-; (32–44); —	Yearly incidence rates: 24–32 per 100 000
Fenton 1988120	2 (DSM3, DSM3R)	532; Inpatients in long-term residential setting; follow-up (15 y (2–32), N = 146 of 164 schizophrenics)	31/34; (31–34); —	Outcome (H, P, S): no differences in outcome
Hwu 1988121	2 (DSM3, ICD9)	137; Inpatients with functional psychiatric disorder; follow-up (7 y, N = 127)	32/63; (36–46); κb = 0.50	Diagnostic stability high. Outcome (P, S): ICD9 more favorable than ICD3
Gerbaldo 1989122	5 (DSM3, FC, Feig, ICD9, RDC)	100; Inpatients with endogenous psychosis	-/-; (30–66); Against FC: κb (0.37–0.86)	Comparison with FC process psychoses: most FC process psychoses were schizophrenia by other definitions
Goodman 1989123	3 (DSM2, DSM3R, Tsuang-paranoid)	78; discharged DSM2-schizophrenia patients (37 paranoid); follow-up (2 y, N = all)	DSM3: 62%; paranoid subtypes: 9/40; (17–29); —	Outcome (H): more inpatient days for DSM2 paranoids and DSM3R nonparanoids
Möller 1989124	3 (DSM3, ICD8, RDC)	183; Inpatients with ICD8 functional psychoses retrospectively rediagnosed; follow-up (5–8 y)	Follow-up: -/-; (43–57); Against ICD8: κ (0.20–0.63)	Outcome (H, P, S): DSM3 schizophrenia poorest GAS outcome
US Soviet study 1989125	3 (DSM3R, USSR chart, USSR current)	27; USSR forensic psychiatric patients	15/89; (15–89); κb (0.04–0.52)	—
Leboyer 199025	4 (DSM3, DSM3R, ICD10, Tsuang)	104; DSM3R schizophrenia members of 49 families; follow-up (13.7 y [1–44], N = all)	100/100; 100; Subtypes: κ (0.57–0.96)	Subtype stability: fairly good by all, highest for patients with hebephrenia
Ni Nuallain 199073	2 (Catego, ICD8)	689 patient sample with ICD8 schizophrenia diagnoses; demographic design	14/100; (14–100); —	1-y prevalence: Catego S-class: 10 and ICD8: 73 per 10 000
Keks 1990,57 199258	11 (Bleu, Cloninger, DSM3, Feig, Flex, FRS, Kraepelin, Langfeldt, Mbleu, RDC, Taylor)	44; Acutely psychotic men (and 28 healthy controls)	7/100; (36–70); —	Basal PRL concentration: lower in RDC, DSM3, and others. Haloperidol reaction on PRL: lower by all definitions except FRS and Bleu.
Copolov 1990,37 McGorry 199233	12 (Bleu, Cloninger, DSM3, Feig, Flex, FRS, Kraep, Langfeldt, Mbleu, RDC, Taylor)	176; Recent onset functional psychosis	-/-; 8 Definitions: (20–73); κ (–0.27–0.67)	Clusters created by explorative multidimensional scaling: (for men) one cluster formed by definitions excluding, and another cluster by definitions permitting affective symptoms. Sex ratio: sex difference by Flex
Peralta 199153	3 (Bleu, FRS)	86; RDC schizophrenia	49/100; (51–63); —	Association with basic symptoms (FCQ): higher in FRS than in Bleu
Wetterberg 1991126	8 (DSM3, DSM3R, Feig, Flex, FRS, Pichot, RDC, Taylor)	51; Patients with psychiatric symptomatology (single-pedigree study)	-/-; (61–100); —	—
Jablensky (WHO 10-country study) 1992127	3 (ICD9, Catego SPO, Catego S+)	1379; Patients with psychotic symptoms or behavior; follow-up (2 y)	50/98; (53–92); κb (0.06–0.42)	Cross-center Catego and ICD subtype variations
Dollfus 1992128	11 (Catego, DSM3R, Feig, Flex, FRS, ICD9, Langfeldt, NHSI, RDC, Taylor, VRC)	51; Nonorganic and nonaffective DSM3R psychosis (present or past)	-/-; (22–78); —	Presence of symptoms: DSM3R, ICD9, and others included patients with negative and depressive symptoms. Phase of illness: ICD9, FRS, and others included more patients with acute symptoms.
Peralta 199234	21 (Bleu, Catego, Cloninger, DSM3, Edwards, Feig, Flex, FRS, Guze, Kraep, Langfeldt, MBleu, Newmark, Pull, RDC, Taylor, VRC, Willis, Yusin)	118; Inpatients with schizophrenia	16/100; (36–88); 4 Definitions: κ (0.13–0.66)	Association with basic symptoms (FCQ): positively with FRS but negatively with DSM3R
Farmer 1992129	11 (Crow, DSM3, DSM3R, Farmer, Feig, Flex, FRS, Pull, RDC, Taylor, Tsuang)	397; Psychotic inpatients	-/-; 8 Definitions: (29–74); —	—
Iacono 199268	5 (DSM3, Feig, Flex, ICD9, RDC)	175; First-episode cases in a large city	-/-; (17–65); —	Incidence rates: 7.4–15.0 per 100 000; Male to female risk ratio: 2.64–3.47
Hiller 199312	2 (DSM3R, ICD10)	100; Inpatients with ICD8 endogenous psychosis	-/-; (30–44); —	—
Keks 199359	11 (Bleu, MBleu, Cloninger, DSM3, Feig, Flex, FRS, Kraep, Langfeldt, RDC, Taylor)	26; Acutely admitted schizophrenia patients	4/100; (23–62); —	α2-adrenergic receptor sensitivity by measuring growth hormone response to clonidine: lower only by Bleu, Cloninger, FRS, Langfeldt, MBleu, and Taylor
Castle 199367	5 (DSM3, DSM3R, Feig67,, ICD9, RDC)	470; First-contact nonaffective psychosis	-/100; (29–100); —	Incidence rates: 6.0–25.2 per 100 000; Male to female incidence rate ratio: 0.5–2.5 (< 45 y: >1; > 45 y: <1)
Strik 1993130	2 (DSM3R, Leonhard)	18; Remitted schizophrenia inpatients (+18 controls)	61/100; (61–100); —	P300 amplitudes: Leonhard: significantly lower amplitude than controls
Deister 1993,131 199423	4 (Andreasen, DSM3R, FRS, ICD10)	148; Patients with narrowly defined schizophrenia; follow-up (23 y (10–50), N = 144)	Follow-up patients: 2/100; (22–100); —	Long-term outcome (H, P, S): 93% persisting alterations. Highest discrimination for DSM3R. FRS had no prognostic value; Subtypes: paranoid and positive subtypes best outcome
Kety 1994,9 Kendler 199410	2 Kety: Kraep-Bleu- DSM2; Kendler: DSM3	76 index and 76 control adoptees and their biological and adoptive relatives (national sample); index adoptees originally diagnosed within a Kraep- Bleu-DSM2 schizophrenia spectrum	-/-; (41–62); —	Prevalence of schizophrenia spectrum disorders in biological vs control relatives: significantly higher by both definitions. Higher, though insignificantly, by DSM2 than by DSM3
Dollfus 1994132	14 (Bleu, Catego, DSM3R, Feig, Flex, FRS, ICD9, ICD10, Langfeldt, NHSI, Pull, RDC, Taylor, VRC)	15; Patients (11 in an acute phase of illness, 14 hospitalized)	-/-; —; —	Concordance between diagnoses by medical examiner and by computer: excellent (κ = 0.63–1)
Wciórka 1995,133 1995134	5 (Bleu, DSM3, FRS, ICD10, VRC)	167 Inpatients with delusional syndrome; follow-up (8.7 y, N = 107)	11/93; (26–83); —	Outcome (H, P, S): DSM3 connected with higher intensity of residual symptoms
Almeida 1995135	11 (Catego, DSM3R, DSM4, Feig, Flex, FRS, ICD10, Langfeldt, NHSI, RDC, Taylor)	47, Patients with ICD9 late paraphrenia (+33 controls)	-/100; Probable or definite: (46–100); κ (0.02–0.57)	—
Davies 1995136	(1) 2 (Feig, non-Feig-ICD10) and (2) 5 (DSM3, DSM3R, Feig, ICD10, RDC)	45; Mothers with schizophrenia (past/present) admitted to a mother-baby unit	-/-; (36–82); —	Admission with acute post partum illness episode: in 43% of non-Feig ICD10, but none of Feig schizophrenics.
Craddock 1996137	2 (DSM3R, RDC)	100; 50 Patients from affective and 50 from schizophrenic families	-/-; (26–27); κ (0.72–0.80)	Agreement between OPCRIT diagnoses and consensus best-estimate lifetime diagnoses: good to excellent agreement (κ = 0.93–0.97)
Harvey 199672	2 (DSM3R, Feig)	980; Prevalence survey. Demographic design	37/62; (44–55); κ = 0.72	Prevalence: 29–31 per 10 000
Hill 1996,138 Roberts 1998139	6 (DSM3R, DSM4,* Feig, FRS, ICD10, RDC)*Roberts	83; Subjects with antemortem DSM3R schizophrenia, rediagnosed postmortem; 57% suicide	5 Definitions: 21/69; 6 definitions: (42–70); 5 definitions: κ (0.32–0.64)	Validation of antemortem diagnoses of schizophrenia by polydiagnostic reassessment: disagreement
Faraone 1996,18 Nurnberger 1994140	2 (DSM3R, RDC)	260; Patients with schizophrenia, schizoaffective and affective psychosis (intrasite study: 179, intersite study: 81)	-/-; (9–19); —	Latent class analysis: Excellent sensitivity and specificity of both definitions. Confusability estimates: DSM3R schizoaffective subtypes often confused with schizophrenia
Williams 1996141	12 (Crow, DSM3, DSM3R, Farmer, Feig, ICD10, NHSI, Pull, RDC, Taylor, Tsuang)	30; A range of diagnoses including nonpsychotic	13/70; (30–70); —	—
Lindström 199771	4 (DSM3, DSM3R, DSM4, ICD10)	Long-term DSM3R functional psychosis in a catchment area; demographic design	-/-; —; —	1-y prevalence of schizophrenia: 49–55 per 10 000
Mason 1997,48 Harrison 1996142	4 (Catego, DSM3R, ICD9, ICD10)	99; First-contact patients; follow-up (13 y, N = all)	-/-; Onset: (31–68); κ (0.13–0.77)	Diagnostic stability: DSM3R and ICD10: high specificity. Outcome (P, S): significant only for DSM3R and ICD10. Effect of duration criteria: a 6-month criterion improved predictive validity.
Jeffreys 1997143	2 (DSM3R, Feig)	Patient samples from 2 censuses of people with a broad clinical diagnosis of schizophrenia	283 Patient sample: 36/62; (39–60); κ = 0.63	Point prevalence (age 15+): broad schizophrenia: 59, DSM3R: 35, and Feig: 34 per 10 000
Kendler 199855	2 (DSM3R, Kendler)	343; Patients with broadly defined schizophrenia and affective illness (+ matched controls)	-/-; DSM3R: 37; Latent classes: schizophrenia 26, Hebephrenia 3; —	Latent class analysis, risk of illness in relatives: highest risk for schizophrenia in relatives of hebephrenia class patients
Maslowski 1998144	12 (Bleu, Catego, Dongier, DSM3R, Edwards, Flex, FRS, Kraep, Langfeldt, MBleu)	113; Schizophrenia patients, 57 colored and 56 black individuals	-/-; —; —	Diagnostic consensus: core symptoms remained the same between 2 ethnic groups but qualitative differences
Wciórka 1998145	2 (DSM4, ICD10)	105; Schizophrenia patients hospitalized in acute phase	83/100; (86–97); 83%	Comparison of diagnostic and symptomatological profiles: minor differences
Cardno 1999,63 200264	4 (DSM3R, FRS, ICD10, RDC)	224 twin pairs (106 MZ); twins with lifetime history of psychosis	-/-; Twin 1: (42–48); —	Twin concordance rate: 0.41–0.43 (FRS: 0.21); lifetime morbid risk: 0.75–0.84; heritability estimates: 0.83–0.87 (FRS: 0.71)
Amin 199940	2 (DSM3R, ICD10)	168; First-contact psychotic patients; follow-up (3 y, N = 161)	-/-; (25–34); —	Positive predictive value: 82–83%; concordance between onset and follow-up diagnosis: κ = 0.46–0.54
Pfuhlmann 1999146	3 (ICD10, DSM3R, Leonhard)	22 MZ and 25 DZ twin pairs; twins hospitalized with ICD9 and DSM3R schizophrenia spectrum psychoses	-/-; (6–32); —	Twin concordance: Leonard systematic schizophrenia: absent in MZ and all DZ patients discordant—therefore impossible to calculate concordance rates
Azevedo 1999147	2 (DSM3R, ICD10)	140; Subjects from bipolar and schizophrenia pedigrees (100), and schizophrenia patients (40)	-/-; (46–47); —	Agreement between OPCRIT diagnoses and consensus best-estimate lifetime diagnoses: excellent (κ = 0.81–0.83)
Peralta 1999,148 2003149	1999: 2 (DSM3R, Feig); 2003: 2 (DSM4, ICD10)	660; Inpatients with psychotic symptoms; iIndex episode and lifetime psychopathology ratings	-/-; (53–64), Feig not included; Good to excellent	1999: Prevalence of FRS: FRS did not increase likelihood of DSM3R and Feig schizophrenia; 2003: Latent class analysis: concordance of between ICD10 and a schizophrenia lifetime class: κ 0.43; between ICD10 and a schizophrenia index episode class: κ 0.61
Allardyce 200070	3 (DSM4, ICD10)	Incidence rates of schizophrenia over time in SW Scotland; demographic design	-/-; —; —	Incidence rates over time (20-y period): falling rate of clinical, but not of OPCRIT diagnoses
Forrester 200122	5 (DSM3R, Feig, ICD10, RDC)	204; Patients discharged with an ICD9 diagnosis of functional psychosis; Follow-up (8.2 y (5 admissions), N = all)	-/-; First admission: (18–29); fifth admission: (30–50); —	Diagnostic stability:1–2 admission 70–84%; 1–5 admission 58–96%; ICD9 highest and ICD10 lowest
Jansson 200239	8 (DSM3, DSM4, Feig, Flex, ICD9, ICD10, RDC, VRC)	155; First admissions (one third clinically psychotic)	Excluding simple schizophrenia: 9/70; (24–57); κ (0.24–0.82)	Concurrent validity: ICD9 was associated with family history of schizophrenia and “trait” formal thought disorder (unlike ICD10)
Häfner 2003150	2 (Catego, ICD9)	232; First-illness episodes of a broad ICD9 schizophrenia; follow-up (5 y, N = 112)	-/-; (73–87); —	Sex ratio: differences nonsignificant
Modestin 2003,7 Bleuler 197897	6 (DSM3R, DSM4, FRS, ICD10, MBleu, RDC)	205; Schizophrenia inpatients from M. Bleuler's long-term study (N = 208); follow-up (10 to >20 y; 202 rediagnosed patients)	-/-; (69–92); κ (0.06–0.99)	Outcome (course prognosis): with the modern definitions the proportion of patients with undulating course and recovery slightly decreased. Correspondence with MBleu as project diagnosis: κ = 0.06–0.24
Jäger 2004151	2 (DSM4, ICD10)	218; Inpatients with functional psychosis; follow-up (15 y, N = 201)	23/29; (23–29); κ = 0.86	Outcome (P, S): no marked differences in outcome; incomplete delimitation of transient/episodic psychoses from schizophrenia
Barrett 200574	3 (DSM4, ICD10, RDC)	Cases with psychotic disorder in a catchment area (in Sarawak)	-/-; —; —	Prevalence rates of treated schizophrenia: 18–35 per 10 000; age corrected (to age 55) 42–83 per 10 000
Jakobsen 2005,152 200638	7 (DSM3, DSM3R, DSM4, Feig, FRS, ICD10, RDC)	100; Patients with chronic functional psychosis	-/-; (69–98); κ (–0.10–0.89)	Cooccurrence of affective and psychotic symptoms: the elimination of OPCRIT item 52 increased the concordance of schizophrenia spectrum disorders
Peralta 200556	23 (Bleu, Catego, Cloninger, DSM3R, DSM4, Edwards, Feig, Flex(6), FRS, Guze, ICD10, Kraep, Langfeldt, MBleu, Newmark, NHSI, Pull, RDC, Taylor, VRC, Willis, Yusin)	660; Patients with psychotic symptoms (= Peralta 1999,148 2003149)	-/-; (29–87); Concordance poor	Factor analysis, 3 factors had substantial interpretation: a general schizophrenia factor, a Schneiderian factor, and a Bleulerian factor
Stompe 2005153	4 (Bleu, DSM4, ICD10, Leonard)	220; Consecutively admitted patients with schizophrenia	100/100; 100; —	Subtype prevalence: variation of subtype frequencies, especially catatonic and hebephrenic subtypes

Note. DSM, Diagnostic and Statistical Manual of Mental Disorders; ICD, International Classification of Diseases.

^aThe diagnostic abbreviations are explained in table 2. As some systems give rise to more than one definition (eg, Flex(5) and Flex(6)), the total number of definitions may be greater than the number of abbreviations.

^bCalculated from article data.

^cAs modified by Tsuang.¹⁵⁴

Diagnostic Definitions

The polydiagnostic studies used approximately 40 different diagnostic definitions of sz and related disorders (2–23 in each study, median = 4). An overview of the definitions is shown in table 2. The formal criteria of these definitions differ; table 3 compares the criteria of some selected definitions.

Table 2.

Diagnostic Abbreviations

Andreasen	Negative and positive schizophrenia, Andreasen and Olsen155
Astrup	Astrup et al156
Bland	Bland and Orn42
Bleu	Eugen Bleuler84
Catego	Catego (narrow or nuclear schizophrenia = S+, broad = S+, P+, S?, P?, and O?), Wing et al157
CDC	Composite Diagnostic Checklist Criteria41
Cloninger	Cloninger et al158
Crow	Crow159
Dongier	Acute delusional psychosis, M. Dongier160
DSM2	DSM-II, APA161
DSM3	DSM-III, APA6
DSM3R	DSM-III-R, APA162
DSM4	DSM-IV, APA163
Edwards	“North America,” Edwards161,164
Farmer	Farmer et al165
FC	Frankfurt Classification System166
Feig	St Louis Criteria, Feighner et al88
Flex	Flexible system, IPSS, WHO167
Forrest	Forrest and Hay168
FRS	First-rank symptoms, Schneider87
Guze	Guze et al169
ICD8	ICD-8, WHO170
ICD9	ICD-9, WHO171
ICD10	ICD-10, WHO172
Kendler	Latent classes55
Kraep	Kraepelin85
Langfeldt	Langfeldt173
Leonhard	Leonhard174
Mbleu	Manfred Bleuler175
McKeon	McKeon cluster, IPSS, WHO36
Newmark	Newmark et al176
NHSI	New Haven Schizophrenia Index177
Pichot	Delusional Attack178
Pull	Critères empiriques français179,180
RDC	Research Diagnostic Criteria, Spitzer et al181–183
SI	The Schizophrenic Index184
TAC	Texas Actuarial Checklist185
Taylor	Taylor and Abrams107,186
Tsuang	Tsuang and Winokur 187
USSR	Snezhnevsky186, Holland and Shakhmatova-Pavlova189
VRC	Vienna Research Criteria, Berner et al4
Willis	“Great Britain,” Willis and Bannister161,190
Yusin	Yusin et al191

Note. DSM, Diagnostic and Statistical Manual of Mental Disorders; ICD, International Classification of Diseases.

Table 3.

Comparison of the Diagnostic Criteria of Selected Schizophrenia Definitions

			Duration Criteria			Symptom Criteria
Name of Schizophrenia Definition/Diagnostic System	Author/Year	Operational Criteria	Illness	Psychosis	Exclusion of Affective Disorder	First-Rank Symptoms	Bizarre Delusions	Formal Thought Disorder	Autism	Blunted/Inadequate affect	Disturbance Self or of Personality
Schizophrenia	Bleuler 1908/191184	−	−	−	−	−	−	+	+	BI	+
St Louis diagnostic criteria	Feighner 197288	+	6 mo	−	+	−	−	+	−	−	−
New Haven Schizophrenia Index	Astrachan 1972177	+	−	−	−	−	−	+	+	BI	−
Flexible system	Carpenter WHO-IPSS 1973167	+	−	−	−	−	+	+	−	BI	−
Present State Examination/Catego S+	Wing 1974157	+	−	−	−	+	−	−	−	−	−
Research Diagnostic Criteria	Spitzer 1975,181, 182 1978183	+	−	2 wk	+	+	+	+	−	B	−
ICD-9	WHO 1978171	−	−	−	−	+	−	+	+	BI	+
DSM-III	APA 19806	+	6 mo	Active phase	+	+	+	+	−	BI	−
Vienna Research Criteria	Berner 19834	+	−	−	−	−	−	+	−	B	−
DSM-IIIR	APA 1987162	+	6 mo	Active phase	+	+	+	+	−	BI	−
ICD-10	WHO 1993172	+	−	1 mo	+	+	+	+	−	BI	−
DSM-IV	APA 1994163	+	6 mo	1 mo	+	+	+	+	−	B	−

Note. +, present; –, not present, DSM, Diagnostic and Statistical Manual of Mental Disorders; ICD, International Classification of Diseases.

Inclusion Criteria of the Individual Studies

58 studies (63%) dealt primarily with psychosis, the 11 of which (12%) with first-admission or recent onset psychosis. 34 studies (37%) included broad groups of patients and population subjects.

Psychopathological Ratings

The information about the details of psychopathological rating procedures was typically inadequate, except for listing the rating scales. 45% of the studies explicitly mentioned psychiatrists as raters, a further 13% used groups of raters with varying professional backgrounds, and 42% gave no information on the education of the interviewers.

In 26% of the cases, the rating was performed solely on the basis of hospital charts, in 39% exclusively on the basis of patient interviews, and in the remainder based on composite sources of information.

Reliability

The expectation of increased diagnostic reliability was what justified the introduction of operational definitions, and the DSM-III field studies did indeed present a high reliability level for sz (81%⁶), but the methodology was loose structured and no further field studies were presented for the later DSM revisions to clarify this issue. However, the diagnostic interrater reliability was assessed in less than half of the polydiagnostic studies, usually in the form of Cohen's kappa coefficients, which were, not surprisingly, somewhat better for the more recent (from Research Diagnostic Criteria [RDC] onward) operational definitions than for older definitions (Modestin et al,⁷ Kirk and Kutchins,⁸ cf. Kety et al⁹ vs Kendler et al¹⁰), generally labeled “good” or even “excellent.” Other forms of reliability checks (eg, test-retest) and other expressions of reliability (eg, symptom agreement) were rarely presented.

Before exploring the question of reliability, one should realize that there are 2 major, overlapping sources of a diagnostic disagreement: (1) criterion variance, which refers to the differences in the raters' use and interpretation of the diagnostic criteria, and (2) information variance, referring to the quality and quantity of the originally collected psychopathological information. The significance of information variance is illustrated by higher kappas found in rating live or videotaped interviews than in rating hospital charts¹¹ and by the fact that the reliability of rating case records remained only moderate even when using structured checklists.¹² Brockington¹³ suggested that low interrater reliability for Feighner's and New Haven definitions in the Camberwell sample was caused by their complexity, which can be seen as an effect of criterion variance. As a rule, a diagnosis based on a few simple items becomes easily reliable compared with the diagnostic algorithms defined by many and interacting features.

Unfortunately, the structure of reliability was rarely discussed, and only a few studies allowed a more detailed reliability examination. In a unique study, Strakowski¹⁴ showed that a lack of reliability between the clinical and the SCID-P (Structured Clinical Interview for DSM-II-R—Patient Version)–generated diagnoses could be partitioned into 58% caused by the information variance and 42% caused by the criterion variance. Unfortunately, such distinctions and explorations of the sources of variance are typically not performed nor discussed. Yet, if a creation or a revision of diagnostic criteria is motivated by reliability concerns, the emphasis should be focused on the criterion variance because the information variance is basically related to the comprehensiveness of the assessment.

Reliability is not an intrinsic property of the diagnostic definition. Needless to say, unreliability may be related to multiple factors, including skill and education of the interviewer. Reliability is higher in research settings but does not ensure reliability in clinical practice. Furthermore, reliability acquired through training on clinical samples cannot be unproblematically extrapolated to population studies where the majority of subjects do not suffer from any mental illness, or suffer from specific psychopathology but unaccompanied by dysfunction or distress, or where the subjects are prone to hide their symptoms. Moreover, the exact significance of quantifying reliability is not unequivocal. Thus, the magnitude of kappa coefficient may reflect differences in prevalence rates.¹⁵ Kirk and Kutchins ⁸ demonstrated that a kappa of the same magnitude may be presented by different adjectives (eg, good or excellent), depending on the agenda of the individual study. Finally, the conventional wisdom of low reliability precluding validity¹⁶ is not invariably true. Some authors demonstrated that diagnostic validity is possible even in the case of low reliability, if the sensitivity is low and specificity is high.^{17, 18}

Frequencies of Specific Diagnoses

Variation in frequencies between definitions.

The studies demonstrated a wide range in the proportions of patients fulfilling the criteria for the individual definitions of sz (eg, Strauss and Gift¹⁹: 1–25%; Lewine et al²⁰: 2–60%). Such differences in the frequency and hence in the inclusiveness of the definitions reflect the variation in the diagnostic criteria. The influence of the duration criteria and the exclusion of affective syndromes were illustrated by a shift from DSM-II (having no such criteria) to the criteria of RDC and DSM-III.²¹ DSM-II sz was often repartitioned as affective, schizoaffective, and schizophreniform disorders.

A DSM-IV and ICD-10 reanalysis of the Burghölzi sz sample, originally diagnosed by Eugen and Manfred Bleuler, showed that the sz diagnosis was retained in nearly in all cases as the contemporary spectrum diagnoses (sz, schizoaffective disorder, schizotypal personality disorder).⁷

Interstudy variation.

There was a striking interstudy variation in the proportion of patients fulfilling a given diagnosis of sz. Differences in study design and inclusion criteria were primarily responsible for this variation. The number of studies allowing an assessment of frequencies of the contemporary definitions was limited. Across 12 studies, the proportion of DSM-III-R sz varied from 24 to 100%, lowest in a group of patients with “functional psychosis²²” and highest in patients with “narrowly defined schizophrenia.²³” Corresponding figures are found for ICD-10 sz.

The samples composed of the patients selected because of their sz diagnosis were (tautologically) frequently diagnosed as having sz by all applied definitions.^{24, 25} Selection of chronic sz patients resulted in frequent sz diagnosis even by Feighner's conservative definition.¹¹ In fact, a comparison of different samples of patients demonstrated that the proportion of Feighner sz increased with chronicity, whereas it was not the case for the frequencies of Schneider's first-rank symptom (FRS)—Berner et al²⁶ and Lenz et al²⁷ vs Cernovsky et al²⁸ and Landmark et al.^{29 , 30}

Diagnostic Concordance (47 studies)

Substantial differences in concordance between the sz definitions were demonstrated in studies comparing the various preoperational definitions.^31–34 Yet, between related systems, there was a considerable concordance.^{7, 31} Some diagnostic concentricity was seen between related definitions. Thus, in one study, almost all Feighner cases fulfilled also DSM-III criteria.³³ Cases fulfilling most of the definitions of sz and, consequently, yielding the highest concordance were often named “core schizophrenia” cases. In one study,³⁵ such cases were found to suffer from paranoid sz. The concordant group of the IPSS patients was characterized by a higher percentage of males and of single patients, a psychopathological profile with more hallucinations, delusions, and flatness of affect, fewer depressive symptoms, precipitating factors, and previous inpatient treatments.³⁶ Uniforming the patient sample tended to increase the concordance between the definitions.

Restricting the sample to a group of patients with illness duration longer than 6 months increased the concordance kappa between definitions having different duration criteria.³⁵ In one study, the concordance was increased by widening the sample to all first admissions and by eliminating the 3 strictest definitions.¹³ Definitions excluding affective symptoms were demonstrated to form a cluster with a higher kappa than the cluster formed by the definitions that permit them.³⁷ In a sample of chronic psychotic patients, the elimination of the OPCRIT item 52, “co-occurrence of psychotic and affective symptoms,” increased the agreement of the sz spectrum disorders.³⁸ Among all studies of the present review comparing diagnostic concordance kappas (N = 34), values above 0.80 were found exclusively in those that included chronic psychotic patients but not in first-onset psychotic patients and mixed groups of patients (Fisher exact test: P < .005).

Validation

78 studies (85%) presented validation data. The most frequently occurring measure of validation was the predictive power of diagnostic definitions. However, true concurrent validation—be it through neurobiological markers or other relevant measures that do not enter into the diagnostic definition such as family history of mental illness, psychometric measures of formal thought disorder, or subjective sense of self-dissolution³⁹—was rare.

Outcome

24 studies (28%) compared the outcome of different sz definitions. The majority of the outcome periods were longer than 5 years. The outcome variables investigated were the prediction of the course of illness, the number of readmissions, symptomatology levels, diagnostic stability, and of social and functional outcome.

Diagnostic stability as a measure of outcome (6 studies) was usually calculated as positive predictive value. Several studies showed high stability of the operational definitions, such as DSM-III-R and ICD-10.⁴⁰

Conservative definitions were found to be predictors of poor outcome, but tautologically, the notion of conservatism is often dependent on the chronicity of course. This applied first of all to Feighner's criteria.^41–44 Broad definitions such as The New Haven Schizophrenia Index, on the other hand, did not predict the outcome.^{13, 31, 42, 45, 46} Such diagnoses embrace favorable as well as poor outcome cases; conservative diagnoses only include the latter group. The duration criteria of the diagnostic algorithm influence the predictive validity. Thus, the 6-month duration criterion has been demonstrated to increase predictive validity in terms of diagnostic stability.^{12, 47, 48} Elimination of affective components in sz tended to result in an aggregation of chronic, nonepisodic, and therefore stable forms of illness.^{49, 50}

Schneider's FRS, playing a central part in the contemporary sz definitions, resulted in a relatively inclusive sz concept that did not predict the outcome.^{13, 23, 27, 31, 45, 46} In comparing DSM-II and DSM-III, the former was found to be more inclusive and indicative of a more favorable outcome. The DSM-III appeared to exclude many females with favorable outcome.⁵¹

Psychopathological Validation

In a few studies, concurrent validity was established by relating sz definitions with traditional sz symptoms or traits such as Bleuler's fundamental symptoms, Schneider's FRS, Huber's basic symptoms, and premorbid adjustment.

ICD-9 sz when compared with ICD-10 was associated with formal thought disorder³⁹ and with self-disorders and basic symptoms (L.B.J and J.P, unpublished data from the same study).

In a comparison of 6 definitions of sz, Bleulerian fundamental symptoms were found to be more important for the diagnosis than Schneiderian FRS.²⁶ In one study, Schneider sz was associated with better premorbid adjustment than non-Schneider sz.³² The significance of basic symptoms assessed by Frankfurt Complaint Questionnaire (FCQ)⁵² seemed more ambiguous,^{34, 50, 53} probably, because of the methodological shortcomings of the FCQ.

Cluster, Latent Class, and Factor Analyses

In the IPSS,³⁶ a McKeon cluster analysis of the present state examination (PSE) data resulted in 10 clusters. Some ICD-8 sz subtypes tended to be concentrated in certain clusters. Some clusters were common to all centers, others only in a small number of them. Three clusters were selected to make up a sz definition for further analyses together with de ICD-8 and Catego-S diagnoses.

Latent class analysis⁵⁴ was carried out in a handful of studies. In an attempt to explain test-retest reliability findings, Faraone¹⁸ estimated the sensitivity and specificity of RDC and DSM-III-R diagnoses to latent classes. Sz according to both systems had high kappas and excellent sensitivity and specificity. Kendler⁵⁵ compared classes generated by a handful of OPCRIT items collected in the Roscommon Family Study with DSM-III-R diagnoses. The classes which emerged resembled well-known diagnostic categories such as classic (Kraepelinian) sz, hebephrenia, and schizophreniform disorder. Eighty-four percent of cases classified as classic sz were also so diagnosed by the DSM-III-R. The classes were validated against the familial risk of illness. The risk for sz and sz spectrum was significantly increased in relatives of all probands classes except major depression and, especially, marked in the relatives of hebephrenia-class patients (sz 16.1%, sz spectrum 45.5%).

Factor analysis of diagnostic variables of 23 sz definitions applied by Peralta⁵⁶ to 660 psychotic patients yielded 3 interpretable factors (a general sz factor, a Schneiderian factor, and a Bleulerian factor) explaining 58% of the variance, which was found to support a dimensional approach to sz.

Biological Parameters

Only a few studies related biological findings to multiple diagnoses. Assuming that the prolactin-releasing potency of a drug corresponds to its antipsychotic potency, Keks^{57, 58} found prolactin concentration to be lower in patients fulfilling criteria precluding affective syndromes.

In measuring the growth hormone response to the injection of clonidine as an expression of α₂-adrenergic receptor sensitivity, Keks⁵⁹ found that most of the definitions associated with blunted response did not preclude affective symptomatology.

Heritability

Heritability served as a measure of validation in a few studies.

Twin studies.

Gottesman and Shields, examining twin concordance as an expression of heritability, found both monozygotic (MZ) and dizygotic (DZ) concordance highest using the broadest definitions (among nonoperational diagnoses of 6 clinicians) but the best MZ:DZ discrimination using “middle-of-the-road” criteria.^{60, 61} However, the emphasis on maximizing MZ:DZ concordance ratio is only meaningful on the prior assumption of polyfactorial transmission.

Conservative definitions such as Feighner's were among those with the highest MZ twin concordance whereas FRS were among those with the lowest.⁶² MZ twins diagnosed by the operational definitions had higher concordance and correlation in liability compared with FRS-diagnosed twins.^62–64

Adoption studies.

In a sample of biological and adoptive relatives of index adoptees with sz and of control adoptees, significant differences were found in the prevalence of sz spectrum disorders in biological vs control relatives of index probands both by a Kraepelin-Bleuler-DSM-II definition⁹ and by DSM-III.¹⁰ The percentage of spectrum disorders was higher, though insignificantly, among the relatives of the former than of the latter.

Family history.

Few polydiagnostic studies compared the familial rates of sz. Comparing 4 definitions, Asnis⁶⁵ failed to find significant differences between the familial rates of sz spectrum disorders. In a first-admission sample, ICD-9 sz was found to be significantly associated with family history of sz, whereas ICD-10 was not associated at all.³⁹ Moreover, partitioning of ICD-10 sz³⁹ revealed that sz selectively aggregated in the relatives probands diagnosed by the criterion 2 (an assortment of Bleulerian and second rank symptoms). Kendler's latent class analysis study,⁵⁵ mentioned above, showed a dramatically increased risk for sz in the relatives of the hebephrenia-class probands.

Demography

Incidence.

Four studies calculated the incidence rates of sz to be within a range from 6 to 32 per 100 000 inhabitants.^66–69 The rates varied within each study between the diagnostic definitions. Thus, ICD-9 sz was found to be broader than DSM-III and DSM-III-R, and Feighner's definition was the most restrictive.

Examining the alleged decline in the incidence of sz, Allardyce⁷⁰ found a falling rate of clinical diagnosis over time (20 years) but not the OPCRIT-generated ICD-10 and DSM-IV sz, suggesting that changes in the diagnostic habits have operated to bias the reported rates.

Prevalence.

Lindstrom⁷¹ calculated the 1-year prevalence of sz by 4 contemporary diagnostic definitions to be within the range of 40–47 per 10 000. The prevalence found by Harvey⁷² was 29–31 per 10 000. The 1-year prevalence of the PSE S-class estimated by Ni Nuallain⁷³ was as low as 10 per 10 000 as compared with the 73 of ICD-8 because of the failure of the S-class to identify patients who presented with exclusively negative symptoms. The combination of PSE and lifetime syndrome checklist data increased the PSE S-class prevalence to 39 per 10 000. Among the Iban of Sarawak, Barrett⁷⁴ found rates of treated sz between 18 and 35 per 10 000—age corrected (to age 55) between 42 and 83 per 10 000, and in rural Botswana, Ben-Tovim⁷⁵ found the age-adjusted 1-year prevalence of DSM-III sz to be 43 per 10 000 and of ICD-9 53 per 10 000.

Gender distribution.

40 studies inform about the gender distribution. The mean numbers of male and female patients in these particular studies were 95 and 86 (nonsignificant). Some studies allowed for a comparison of incidence rates, frequencies, and lifetime courses. The highest ratio of male to female incidence rate was produced by the narrow Feighner definition.^{67, 68} Other studies failed to demonstrate the incident sex ratio differences between broad and narrow definitions.^{66, 76} Conservative definitions yielded a significantly greater male to female prevalence ratio.^{20, 51, 67, 77} Patients excluded by the narrow definition were typically favorable-outcome females.⁵¹ Castle⁶⁷ found the male-to-female ratio to be higher than 1 in patients with onset below age 45 and lower than 1 above age 45 in sz definitions requiring a 6-month duration.

Age of onset.

Male patients had a lower age of onset in nearly all definitions,⁷⁶ but narrow definitions seemed to be associated with onset before age 25 in a greater part of the patients than the broad ones.⁷⁷

Discussion

The polydiagnostic studies of the past 4 decades reflect an evolution away from prototypically anchored diagnostic concepts of sz to polythetically oriented definitions, based on the so-called operational criteria. It is, however, necessary to point out that all studies reviewed here—as polydiagnostic comparisons—necessitated a certain operationalization of the examined definitions.

The principal finding of our review is that the degree of concordance between different definitions of sz varies considerably, depending, of course, on the similarity of the criteria. The number of sz cases in a given sample may vary by more than factor 3 when diagnosed by 2 different systems. This is far from trivial and not only because of psychopathological considerations. In fact, etiological research is very frequently performed through comparisons of “schizophrenias” with “nonschizophrenias,” ie, the sample is simply dichotomized into szs and the remainder of the sample. Such procedure may attenuate or otherwise obscure differences of interest because the “nonschizophrenia” group may contain spectrum cases as well as sz cases defined so by other sets of criteria.

The polydiagnostic studies do not provide sufficient validity data to justify claiming a clear superiority of any particular definition over others. In many studies, the percentage of sz cases so diagnosed by all diagnostic algorithms is remarkably low. This subgroup—usually called “core schizophrenia”—appears to us more as a product of severity and impenetrable interactions between the single criteria rather than as being reflective of a class with a particularly strong validity.

What is conspicuously lacking in the polydiagnostic studies is a serious and systematic reflection on the conceptual validity of sz, ie, what we take this illness to be in the very first place.⁷⁸ Empirical phases of validation do not happen in a void but are preceded and constrained by the original typifications of what we take sz to be.^78–83 There are several possibilities: eg, is it an illness mainly defined by trait-like intersubjective displacement, subjective orientation with changes of the worldview (as described by Bleuler's generic term of autism^{84, 81}), compromised unity of consciousness and self-dissolution (Kraepelin^{85, 86}), characteristic psychotic symptoms (a view unjustly ascribed to Schneider⁸⁷), a deteriorating or unremitting course (Feighner⁸⁸), simply a multidimensional construct,^{56, 89} or something else (eg, schizotaxia^{90, 91})?

The issue of affective symptoms represents a special concern in the discussions of conceptual and construct validity. The exclusion of affective components from the picture of sz, despite their clinical reality as ubiquitous symptoms in all stages of sz, has also necessitated a creation of a rather convoluted category of schizoaffective psychosis.⁹² This evacuation of affective symptoms from sz appears as quite arbitrary, and yet as shown by Keks,^57–59 a stratification of sz by presence or absence of affective symptoms may be biologically meaningful. The subdivisions of sz on the basis of biological findings obtained in polydiagnostic studies are in agreement with Bleuler's claim that we deal with a group of szs rather than a single disease.⁸⁴ Such a view gains currently provisional support from genetic studies. Thus, in a family study by Hallmayer et al, a mathematically identified subtype of sz, characterized by pervasive neurocognitive deficit, had a distinct genetic profile.⁹³

Empirical validity is a multidimensional concept comprising pathogenetic and etiologic knowledge (or hypotheses), course, treatment response, etc. Although we have knowledge of a variety of etiologically relevant risk factors in sz, this knowledge has no substantive form, which could permit assessment of causal validity in a polydiagnostic context. Genetic data³⁹ suggest that it is the Bleulerian dimension of fundamental symptoms that is associated with familial aggregation of sz. No molecular genetic studies have so far been included in the polydiagnostic designs.

Predictive validity—exploring outcome and stability of course—is examined in approximately half of the studies. Unfortunately, it is a rather equivocal type of validity. Prediction of course may serve as a validity criterion with an independent a priori assumption that, say, an unremitting course or chronic social dysfunction is constitutive of a given diagnostic entity. The recent duration criteria lead to an automatic exclusion of favorable outcome, acute psychosis. Diagnostic stability in the sense of basically unchanged psychopathological picture as a measure of validity is at odds with the well-replicated findings that 20–30% of patients with sz recover from psychosis (cf. Modestin et al,⁷ Hafner and an der Heiden,⁹⁴ Ciompi and Muller,⁹⁵ Huber et al,⁹⁶ and Bleuler⁹⁷). Psychopathological stability would be relevant as a validating criterion if one were interested in the persistence of the trait features of the illness, indicating structural alterations of consciousness.⁸¹ Therefore, definitions based on trait-like features (eg, Bleuler's fundamental symptoms) appear to be more stable than those based on fluctuating psychotic features (eg, FRS). In the latter case, diagnostic stability means chronic, productive psychosis. The FRS are particularly poor predictors of outcome.^{13, 23, 27, 31, 45, 46} Conservative definitions with inbuilt chronicity (deviant preonset personality) such as Feighner's are more likely to predict uniformly poor outcome. Unfortunately, only few studies made an attempt to examine differential validity of sz by other means than outcome prediction.

A dominating concern of contemporary psychiatry is the quest for reliability of diagnostic categories. The very rise of “operational” definitions in the 1970s was stimulated by the demonstration of alarming US-UK diagnostic disagreements.^{98, 99}

The operational definitions seem to have modestly increased the interrater reliability (eg, Gruenberg et al¹⁰⁰; Kety et al⁹ vs Kendler et al¹⁰). However, reliability is easy to achieve but “it becomes vacuous when it is a primary goal, un-associated with other concerns.¹⁰¹” In the quest for reliability, many domains of psychopathology of sz, once considered as taxonomically and pathogenetically crucial (eg, the notion of autism or formal thought disorder) have been either strongly simplified (converting the “fundamental” schizophrenic symptoms into behaviorally defined “negative symptoms^{86, 102}”) or deleted altogether from the psychiatric idiom (eg, the notion of self or subjectivity¹⁰³).

In conclusion, this review highlights certain steps that seem to us as urgently needed in sz research. There is a need for integrating the rapidly expanding technological means with explicit reflection constrained by phenomenological familiarity with sz. Empirical studies should increasingly lose their exploratory nature and become instead designed to answer more specific and explicit questions.