IN REVIEW

Epidemiology of Schizophrenia

Heinz Hfner

1

, Wolfram an der Heiden

2

Objective: To characterize the epidemiology of schizophrenia.Method: Narrative literature review.Results: Each year 1 in 10 000 adults (12 to 60 years of age) develops schizophrenia. Based on a restrictive and precisedefinition of the diagnosis and using standardized assessment methods and large, representative populations, theincidence rates appear stable across countries and cultures and over time, at least for the last 50 years. Schizophrenicpatients are not born into ecological and social disadvantage. The uneven distribution of prevalence rates is a result ofsocial selection: an early onset leads to social stagnation, a late onset to descent from a higher social status. The mainage range of risk for schizophrenia is 20 to 35 years. It is still unclear whether schizophrenia-like late-onset psychoses(for example, late paraphrenia) after age 60 should be classified as schizophrenia either psychopathologically oretiologically.In 75% of cases, first admission is preceded by a prodromal phase with a mean length of 5 years and a psychotic prephaseof one years duration. On average, women fall ill 3 to 4 years later than men and show a second peak of onset aroundmenopause. Consequently, late-onset schizophrenias are more frequent and more severe in women than in men. The sexdifference in age of onset is smaller in cases with a high genetic load and greater in cases with a low genetic load. Typeof onset and core symptoms do not differ between the sexes. The most pronounced sex difference is the socially negativeillness behaviour of young men.Conclusions: Among the factors determining social course and outcome are level of social development at onset, thedisorder itself (for example, genetic liability, severity of symptoms, and functional deficits), general biological factors(for example, estrogen), and sex- and age-specific illness behaviour.

(Can J Psychiatry 1997;42:139151)

Key Words: schizophrenia, epidemiology, incidence, prevalence, ecology, symptomatology, age at onset, genderdifferences

One hundred years of research efforts have failed to pro-duce biological indicators specific to a diagnosis ofschizophrenia. Studies on schizophrenia morbidity, therefore,continue to rely on descriptive case definitions, and the qual-ity of their results depends on the diagnostic definitions used.

In a historical analysis, Dohrenwend (1) distinguished 3periods of epidemiological studies in psychiatry. Accordingto his methodological standards, only the last period, begin-ning around 1980, has produced valid and transnationally

comparable findings. The standards include a precise, opera-tional case definition, the collection of comprehensive dataon all cases from a sufficiently large, statistically well-documented population, symptom assessment by transcul-turally standardized instruments, and computerized diagnosisindependent of the interviewer. The World Health Organiza-tion (WHO) Determinants of Outcome study (2) was thefirst to satisfy nearly all of these requirements at each studysite in the determination of the incidence of schizophrenia (12centres, 10 countries). Recently, Thornicroft and Johnson (3)have added a further methodological standard that calls forthe assessment of met and unmet needs for care in psychiatricsurveys.

Ecological Epidemiology

With their ecological Chicago study, Faris and Dunham(4) began an important chapter in the epidemiology of schizo-phrenia. The authors found the highest first-admission rates

1Director, Schizophrenia Research Unit, Central Institute of Mental Health,Mannheim, Germany.2Senior Scientist, Schizophrenia Research Unit, Central Institute of MentalHealth, Mannheim, Germany.Address for correspondence: Dr H Hfner, Durchwahl 17 03-726, J 5,Mannheim 68159 Germany

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for schizophrenia in the inner city, characterized by socialdisintegration and low-standard housing. The lowest inci-dence was on the outskirts of the city, in high-standardresidential areas. In the wake of their study, similar zonaldistribution patterns were reported from several Americancities, but also from Oslo, Norway (5), Nottingham, UnitedKingdom (6), and Mannheim, Germany (7). In Mannheim,the incidence of schizophrenia was reassessed 10 to 15 years(8) and 22 to 23 years (9) later. Parallelling the citys stablesocioecological structure, the ecological distribution patternof first-admission rates for schizophrenia proved stable.

Besides the uneven ecological distribution of the rates,individuals with schizophrenia at first admission are usuallyfound to be personally and socially disadvantaged as well.Dohrenwend and Dohrenwend (10) found the highest rates inthe lowest social class in 5 out of 7 first-admission studies,and Eaton (11) found the same in 15 out of 17 studies. In alater metaanalysis of studies on the topic, Eaton and others(12) calculated a ratio of 3 to 1 for the risk of schizophreniabetween the lowest and the highest of 3 social classes.

Social Drift versus Social CausationAlthough time and cause were unclear, the social gradient

provided the impetus for a causal link between severe socialdisadvantage and schizophrenia onset (10,13,14). The social-drift hypothesissocial decline after illness onsetmerelyexplained the uneven social distribution of prevalence rates.Since first admission or first contact, at that time, was takenas the operational definition of the onset of the disorder, anysocial consequences of the emerging disorder were notconsidered.

Retrospectively studying individual ecological mobilitybefore first admission, Dauncey and others (15) found that theecological disadvantage observed in schizophrenic patientsat first admission had emerged, on average, 5 years before.The ecological selection is brought about by a tendency ofindividuals later admitted with a diagnosis of schizophreniato remain during the premorbid period in decaying housingareas, while their healthy and socially more successful peersmove on from these areas into better neighbourhoods. Similarconclusions were drawn by Wiersma and others (16) usingDutch data.

On the basis of the national Norwegian case register,degaard (17) early pointed out that people with schizophre-nia tend to cluster in rapid-turnover and low-status jobs priorto their first admission. He implicated premorbid schizoidpersonality traits in the explanation.

It seems that at least a part of the social disadvantageinvolved in schizophrenia emerges before first admission.The question of it already being present in the patientsparents was investigated by Goldberg and Morrison (18) in amethodologically sound intergenerational study in London.They demonstrated, for schizophrenic men, that the lack ofupward social mobility emerges after birth. In another study,conducted by Turner and Wagenfeld (19) in New York, thefathers of schizophrenic men showed slightly lower socialstatuses compared with controls, but this result is probably

attributable to the selection of a socially disadvantaged studypopulation, that is, first admissions to state mental hospitals.Meanwhile, 3 large studies of birth cohorts from Great Britain(20,21) and Northern Finland (22) followed into the age ofrisk for schizophrenia have demonstrated that schizophrenicpatients are not socially disadvantaged at birth.

Dohrenwend and others (23) tested the alternative hy-pothesis of social causation versus social selection in a metho-dologically sophisticated study in Israel. They foundcompelling evidence for the social selection hypothesis inschizophrenia, in contrast to the risk for major depressivedisorder in women or substance abuse in men.

Hence social causation does not appear to play an essentialetiological role in schizophrenia, as is also indicated by thefairly similar morbidity risk in all the populations investigated(2).Prevalence

Prevalence is a product of incidence and length of illness.Length of illness is determined by various factors, for exam-ple, variation in the life expectancies of the populationsstudied, excess mortality after disease onset, and varyingproportions of symptom-free cases due to differences in treat-ment, so that comparisons of prevalence rates across studiesare difficult. Prevalence rates are primarily used as an indica-tor of the morbidity of a given population and its need forcare.

Table 1 lists selected prevalence studies of schizophreniaand their results according to the following criteria: 1) studiespublished in 1980 or later, 2) population studies or suffi-ciently representative utilization studies (for example, caseregisters).

For the reasons stated above, the marked variation in thetotal rates cannot be interpreted as reflecting differences inthe morbidity of the populations under study. The point versusperiod prevalence rates differ only minutely which, as pointedout by Eaton and others (24), is accounted for by the primarilychronic course of the illness involving only slight annualexcess mortality.

The dependence of the study results on the diagnosticdefinition is reflected in the fact that only 30% of a repre-sentative sample of first-admission cases (N = 276) assignedto a broad clinical diagnosis of schizophrenia according toICD-9 (295, 297, 298.3/4) (the ABC schizophrenia studysample) qualified for a DSM-III diagnosis of schizophrenia(25). The lifetime prevalence rate of 1.5% reported from theEpidemiologic Catchment Area study (26) is probably toohigh. A possible reason is that the assessments wereconducted by lay persons using instruments of lowdiscriminative power (27). The most precise estimates of thelifetime risk so far, though only up to the fifth decade of life,have been reported from the British birth cohort study (28).The directly assessed cumulative prevalence until age 43 was0.63. Assuming that the share of late-onset schizophrenias inthe total schizophrenic morbidity is fairly low (15%), thisfigure presumably represents a fairly close estimate of the true

140 The Canadian Journal of Psychiatry Vol 42, No 2

cumulative lifetime prevalence as based on the ICD-9diagnosis 295.

The prevalence rates for old age probably need to beadjusted. It is still unclear how many of the delusional disor-ders of the old and the very old can be subsumed under thediagnosis of schizophrenia and, thus, be considered part ofthe prevalence and incidence of schizophrenia in these agegroups (29). The reason is that attempts at a precise empiricaldistinction at the psychopathological level have failed.

IncidenceAs stated, incidence rates are the key indicator of morbid-

ity risk. Their distribution patterns across geographic, culturaland social units, family membership, age, and sex alsoprovide some external criteria for testing the validity of adiagnosis (30) and for formulating etiological and pathoge-netic hypotheses.

Since the onset of schizophrenia is a comparatively rareevent, the accurate assessment of incidence figures is faced

with considerable practical and methodological problems.This is especially the case when age distributions are studiedor risks for certain age groups are estimated. To ensureaccuracy, the following preconditions should be fulfilled: 1)the population at risk must be sufficiently large, geographi-cally stable, and statistically well documented to provideexact data on age, sex, and social status for the denominatorin the calculation; 2) the study sample must be representative,that is, comprise all the cases fulfilling the diagnostic criteriaduring the study period; 3) the study sample must be largeenough to cover the whole age-of-risk range for schizophre-nia; 4) the cases should be entered in the study as soon afteronset as possible in order to keep recall deficits, postonsetdeaths, and other distorting effects to a minimum; 5) onsetmust be defined and its occurrence determined precisely. Thecommon administrative definition of onset, first admission tohospital or first psychiatric contact, is flawed by uncertaintyabout the duration of the time period of illness preceding thatevent. The more precise, but still artificial, definition of adiagnostic onset (the time point when a set of diagnostic

Table 1. The prevalence of schizophreniaa

Authors Country PeriodPrevalence per 1000

population Age correctionBabigian (98) USA 1 year 4.1 YesBamrah and others (99) UK 1 year 7.5 NoBebbington and others (100) UK Point 10.9 YesBen-Tovim and Cushnie (101) Botswana 1 year 5.3 NoBland and others (102) Canada Lifetime 0.3 NoBlazer and others (103) USA 6 months 6.0 to 11.0 NoBurnam and others (104) USA 6 months 3.0 to 6.0 NoCanino and others (105) Puerto Rico 6 months 15.0 NoCheung (106) China 1 year 1.9 to 4.7 YesDilling and Weyerer (107) Germany Point 3.9 NoFolnegovic and Folnegovic-Smalc (108) Croatia 3 months 1.5 to 5.1 NoFreeman and Alpert (109) UK 1 year 6.8 NoHalldin (110) Sweden 1 year 6.0 NoHodiamont and others (111) Netherlands Point 7.3 YesHwu and others (112) Taiwan Lifetime 3.1 NoLee and others (25,113) Korea Lifetime 3.1 to 5.4 NoLehtinen and others (114,115) Finland Point 1.3 NoLin and others (116) China Point 4.2 YesMavreas and Bebbington (117) UK Point 13.0 NoMurphy and Taumoepeau (118) Tonga 1 year 0.9 to 1.3 NoMyers and others (119) USA 6 months 6.0 to 11.0 NoNandi and others (120) India Point 2.2 YesShen and others (121,122) China Point 1.8 YesSikanerty and Eaton (123) Ghana Point 1.1 NoTemkov (124) Bulgaria Point 2.8 YesVasquez-Barquero (125) Spain Point 5.6 NoWalsh (126) Ireland Point 9.8 NoWeissman and Myers (127) USA Point 4.0 NoWiderlv and others (128) Sweden Lifetime 0.7 to 5.0 NoZimmerman-Tansella and others (129) Italy 1 year 1.3 No

aAbridged version of a compilation by Warner and de Girolamo (36), supplemented by own review of literature.

March 1997 Epidemiology of Schizophrenia 141

criteria is fulfilled for the first time), proposed by Pogue-Geile(unpublished observation), is an acceptable basis for roughestimates of the incidence. If, however, the intention is todetermine the time point or age of onset precisely, both theprodromal phase and the development of illness before thediagnostic criteria are met must be taken into account.

An ideal approach to studying incidence would be a pro-spective birth cohort design with cross-sectional assessmentsat short intervals. A prospective birth cohort design is adoptedin studies of the offspring of schizophrenic mothers, but forcost reasons, the cross-sectional assessments are carried outat lengthy intervals. Moreover, the incidence rates calculatedfor these high-risk groups do not provide any information onincidence in the population at large. Birth cohorts of generalpopulations were studied retrospectively by Fremming (31)in Denmark and for over 70 years by Helgason (32) in Iceland,but the number of 34 or 36 cases of schizophrenia is too lowfor calculating age-specific risks. The British birth cohortstudy (28) provided population-based first-admission ratesfor schizophrenia until age 43 years, but did not produce dataon the age distribution of onset.

Only in a minority of cases is the onset of schizophreniamarked by conspicuous symptoms. In three-quarters of thecases, the first psychotic episode is preceded by a prodromalphase of several years duration, during which nonspecificsymptoms predominate. The psychotic prephase, too, fre-quently evolves unnoticed by others, at least for some time(33). This means that schizophrenia is currently diagnosableonly after it has started to produce psychotic symptoms andis perceived by the patient himself or herself or by others. Itsonset and all associated variables, such as age distribution ofthe morbidity risk, must therefore be determined retrospec-tively by suitable methods.

The problems involved and possible solutions have beendiscussed by Maurer and Hfner (34) in the context of thestandardized interview developed to address them: Instru-ment for the Retrospective Assessment of the Onset ofSchizophrenia (IRAOS) (35). The interview was designed toproduce data on prodromal signs, symptoms, functional im-pairment, social disability, and objective social developmentfrom 3 sources and on the basis of a time matrix, whichenables accurate timing by means of anchor events.

Population studies are impractical because of the lowmorbidity risk. A 2-stage design should be used, therefore,that is, one which identifies all incidence cases of nonaffec-tive psychosis from all the clinical records of a large, definedpopulation over the course of one or 2 years. For this methodto be accurate, however, the lifetime likelihood of schizo-phrenic patients coming into contact with the mental healthservices of the catchment area must be close to 100%. Thispercentage, depending on the availability and cost of mentalhealth services, is bound to decline with time because of thegrowing proportion of patients with schizophrenia treated bygeneral practitioners. An additional search for incidencecases not in contact with mental health services can improve

epidemiological validity, especially in developingcountries (2).

At the second stage, standardized interviews are adminis-tered to the index population obtained through the initialscreening. The operational accuracy of the diagnosis and allthe other design variables ensured, onset is then assessedretrospectively.

Comparative EpidemiologyTable 2 is based on a review by Warner and de Girolamo

(36) but restricted to studies published after 1980. Ratescalculated with populations not corrected for age are soindicated. The incidence rates range from a minimum of 0.07to a maximum of 7.1. Tempting though it would be to explainthese differences as secondary to regional heterogeneity ofenvironmental or genetic factors, the studies should first becompared for their methodological standards.

In the WHO Determinants of Outcome study (2), allpatients were assessed for psychopathology with a semistruc-tured interview, the Present State Examination (PSE) (37).The PSE is supplemented by a computer algorithm, known asCATEGO, that can be used at several levels of classification.The patients are allocated to 1 of 9 descriptive CATEGOclasses, depending on the prevailing symptomatology as, forexample, S+, representing central schizophrenic conditions(thought intrusion and delusions of control), P (paranoidsymptomatology), or O (other psychoses).

The results from 7 countries are illustrated by data for 8study sites, depicted in Figure 1 in sections II and III. Forcomparison, section I gives the rates from 8 selected nationalstudies. The transnational variability of the incidence ratesdecreases as the stringency of studies increases. The nationalstudies show the greatest variation in methodology, for exam-ple, diagnostic definitions and case findings. In the interme-diate section, annual incidence rates for a broadly defineddiagnosis of schizophrenia (ICD 295 or CATEGO S, P, andO), based on the same sample as in section III, show less butstill considerable variation, whereas in section III, based on arestrictive and highly reliable diagnosis of nuclear schizo-phrenia (CATEGO S), no significant differences can be seen,the annual rates varying around 10/100 000.

Incidence rates of the same size in all populations andcultures studied render a substantial role of cultural, social,or climatic factors in the morbidity risk for schizophreniainconceivable.

Zubin (38) tried to explain this unusual epidemiologicalpattern by assuming that schizophrenia is the common finalpathway arising from a great number of causes. Anothercommon disorder with an almost identical age-corrected in-cidence throughout the world is dementia in old age (39,40),which shows a clear-cut causal heterogeneity, but largelyidentical symptoms.

Age at OnsetIn the majority of studies (age of risk beyond 60 years

unconsidered), the mean age at first contact or first admission

142 The Canadian Journal of Psychiatry Vol 42, No 2

lies between 25 and 35 years for men and women (41,42). Inthe ABC schizophrenia study (43), mean age at onsetaccording to different definitions as assessed by the IRAOSinterview (35) was 24.0 years for the first sign of the disorder,25.5 years for the first negative symptom, 29.0 years for thefirst positive symptom, 30.1 years for a first peak of positivesymptoms (climax of the first psychotic episode), and 30.3years for the first admission to hospital.

Late-Onset Schizophrenia and Late Paranoid PsychosesThe question whether first episodes of schizophrenia also

occur beyond age 60 is still unclarified. A great obstacle toepidemiological studies of nonaffective functional psychosesin old age is not only the diagnosis but also the fact that neitherpsychiatric nor general medical services nor populationstudies guarantee access to all the cases with paranoid orschizophrenic symptoms. This is why the results from recentstudies continue to vary considerably.

Harris and Jestes (44) review of European studies onlate-onset schizophrenia, as well as national Danishcase-register data (41), showed a decrease in first-admissionrates after age 60 based on a clinical diagnosis of schizophre-nia. In contrast, applying the more restrictive DSM-III-Rdiagnosis of schizophrenia, Castle and Murray (29), whorated Camberwell register data for 1965 to 1984, demon-strated a considerable increase in old age, particularly in

women. On the basis of first admissions with a clinicaldiagnosis of schizophrenia to other British registers and to theDutch national case register, van Os and others (45) recentlyfound an increase from about 10/100 000 in the age group 60

Table 2. The incidence of schizophreniaa

Authors Country DiagnosisIncidence per 1000population per year Age correction

Babigian (98) USA Clinical diagnosis 0.94 NoBamrah and others (99) UK ICD 0.19 NoBates and van Dam (130) Canada Clinical diagnosis 0.10 YesDer (76) UK Clinical diagnosis 0.09 to 0.16 NoDilling and others (131) Germany Clinical diagnosis 0.48 YesEagles and Whalley (75) Scotland ICD 0.12 to 0.20 YesFolnegovic and others (132) Croatia ICD 0.27 NoGiel and others (133) Netherlands ICD 0.11 NoHfner (1996, unpublished observations) Germany ICD 0.16 NoHagnell and others (134) Sweden Clinical diagnosis / PSE-CATEGO 0.24 YesJablensky and others (2) Denmark Clinical diagnosis / PSE-CATEGO 0.07 to 0.18 NoJablensky and others (2) India Clinical diagnosis / PSE-CATEGO 0.09 to 0.35 NoJablensky and others (2) USA Clinical diagnosis / PSE-CATEGO 0.09 to 0.16 NoJablensky and others (2) USSR Clinical diagnosis / PSE-CATEGO 0.12 to 0.28 YesJablensky and others (2) Japan Clinical diagnosis / PSE-CATEGO 0.10 to 0.21 NoJablensky and others (2) UK Clinical diagnosis / PSE-CATEGO 0.14 to 0.24 NoJablensky and others (2) Ireland Clinical diagnosis / PSE-CATEGO 0.09 to 0.22 NoKrasik and Semin (135) USSR Clinical diagnosis 0.08 to 0.23 YesKrupinski (1983, unpublished observations) Australia 0.18 YesMunk-Jrgensen (42) Denmark Clinical diagnosis 0.07 to 0.11 NoNinuallain (136) Ireland Clinical diagnosis / ICD / PSE-CATEGO 0.37 NoEaton (137) India 0.58 NoShen (121,122) China Clinical diagnosis 0.11 YesTien and Eaton (138) USA DSM 1.0 to 7.1 No

aAbridged version of a compilation by Warner and de Girolamo (36), supplemented by own review of literature.

Figure 1. Incidence rates from selected national studies and theWHO Determinants of Outcome study per 100 000population, aged 15 to 54 (both sexes), and for a broadand restrictive definition of schizophrenia.

March 1997 Epidemiology of Schizophrenia 143

to 74 to 19/100 000 in the group 75 and over in England andWales and to 25/100 000 for those aged 90 and over in theNetherlands (Figure 2).

There are, however, ongoing controversies whetherearly-onset and late-onset schizophrenia are different orsimilar disorders and which delusional disorders of the eld-erly should be included with late-onset schizophrenia andwhich of them classified separately as, for example, lateparaphrenia, paranoid psychoses, or merely persistent delu-sional syndromes. Behind the question of a valid diagnosis isthe issue of the underlying etiologies or, at least, of thesimilarities or differences of symptoms and course (4650).

Studies focusing on the differentiation of delusional syn-dromes in later life are reviewed in Table 3. Final conclusionsare difficult to draw because of methodological limitations:all of these studies employed small convenience or treatmentsamples (44,47). Often first-episode cases as well as readmis-sions were included or no information was given on this issue.

In none of the recent studies attempting to distinguishbetween primary paranoid disorder and schizophrenia in old

age at the symptom level in sufficiently large studypopulations did the methods adopted produce a clear-cutempirical demarcation (44,51,52).

The main risk factors for paranoid disorders in old age arecognitive and sensory impairment (44,53), whereas inearly-onset schizophrenia, signs of delayed development,including cognitive impairment, predominate. It is thereforereasonable to assume that in early-onset and very late-onsetschizophrenia, respectively, disordered or delayed brain de-velopment and degenerative processes of the brain, in bothinstances ranging from mild to moderate in severity, are thekey risk factors. The reaction pattern of schizophrenia orparanoid psychosis as a common final pathway shows clear-cut psychopathological similarities but also some age-relateddifferences in both periods of life (54).Sex Differences in Age at First-Ever Onset and LifetimeRisk

As early as 1909, Kraepelin observed that women withdementia praecox, when hospitalized for the first time, wereseveral years older than men. In their review of 53 studies,

Table 3. Studies on the psychopathology of late-onset schizophrenia

Author Sample Type of study/assessmentSymptomatology inlate-onset schizophrenia

Risk factors for late-onsetschizophrenia

Fish 1960 (47) All 41 paranoid states> 60 years admitted in 1957,including 9 late-onset and 7early-onset schizophrenia(cut-off 60 years)

Case notes, partly personalexamination

No specific schizophreniasyndrome

Paranoid personality traits

Kay and Roth 1961 (139) 99 admissions > 60 yearsdiagnosed with lateparaphrenia

Case records and clinicalassessment

Auditory hallucinations andmany typicallyschizophrenic symptoms;systematic and fantastic,usually persecutorydelusions; rare incoherenceof thought

Female gender, deafness,personality disorder, fewrelatives

Harris and others 1988 (140) 5 cases aged 56 to 67 yearswith late-onsetschizophrenia (first andreadmissions)

Case study Bizarre (persecutory)delusion, auditoryhallucinations, visualhallucinations, paranoidsubtype

Pearlson and others 1989 (51) 54 late-onset (> 45 years)versus 54 early-onset (young)versus 22 early-onset(elderly); first andreadmissions

Rating of case records More visual, tactile, olfactoryhallucinations, more diversityof hallucinations, morepersecutory delusions; lessaffective flattening, fewerthought disorders

Sensory impairment,schizoid premorbidpersonality, female gender,living alone

Howard and others 1993 (53) 134 late-onset (> 45 years)versus 336 early-onset cases;first admissions

Rating of case records Persecutory and organizeddelusions; third personrunning commentary;auditory hallucinations

Female gender

Mayer and others 1993 (52) 130 first admissions 40 to 63years versus 126 firstadmissions 18 to 23 years

Evaluation of systematic clinicalassessment

More depression; moresymptoms of autonomicnervous system, lesspsychosocial impairment

Female gender

Yassa and Suranyi-Cadotte1993 (141)

20 late-onset schizophrenia(> 45 years) versus 7paraphrenia versus 13late-onset paranoia (firstand readmissions)

Clinical assessment Late-onset schizophrenia:bizarre delusions, auditoryhallucinations; paraphrenia:nonbizarre delusions;late-onset paranoia:nonbizarre delusions, organicconditions

Female gender (alldiagnoses); no increasedsensory deprivation

Jeste and others 1995 (142) 25 late-onset schizophreniaversus 39 early-onsetschizophrenia versus 35normals

Clinical and neuropsychologicalassessment

Paranoid subtype, betterwork adjustment

144 The Canadian Journal of Psychiatry Vol 42, No 2

Angermeyer and Khn (55) found that women at first admis-sion and frequently also at onset, which has been defined andascertained in different ways, were older than men. Figure 3,taken from the ABC schizophrenia study and based on arepresentative sample of 232 first-episode cases, shows asignificant age difference of about 3 to 4 years for all defini-tions of onset. The pooled data of the WHO Determinants ofOutcome study revealed a mean age difference of 3.4 years(56).

A comparison of the distribution patterns of onset for menand women on the basis of ABC study data showed that onsetfor males started to increase somewhat earlier and moresteeply and, after a pronounced peak in the age group 15 to

25 years, steadily fell. Female onsets were slower to increase,reached a lower peak somewhat later in life and, after decreas-ing, peaked again, but less markedly in the age group 40 to45 years. In first-admission rates, a peak would be expectedto occur about 5 years later, which we were able to demon-strate on first-admission rates from the Danish national caseregister (Hfner and others 1996, unpublished observations).The distribution pattern published by Castle and others (57),based on Camberwell case-register data over 20 years, alsodisplayed a second peak of female onsets just prior tomenopause.

Loranger (58), Seeman (59), Lewine (60), and Seeman andLang (61) have previously suggested that the sex differencein age at onset might be accounted for by a protective effectof estrogen. Animal experiments have shown that acute andlong-term estrogen applications actually reduce dopaminer-gic behaviour by attenuating the sensitivity of central D2receptors (62,63). Estrogen effects on serotonin receptors atthe neurochemical and the molecular level (gene expression)have been reported by Sumner and Fink (64) and on glutamatereceptors by Woolley and McEwen (65). In a controlledclinical study of schizophrenic and depressive women withnormal menstrual cycles, Riecher-Rssler and others (66)showed that, when estrogen levels were at their peak, schizo-phrenic and nonspecific symptom measures were signifi-cantly reduced but depressive symptoms were unaffected inboth diagnostic groups of women.

The sex difference in age of onset, however, disappears incases with a high genetic load, as shown by DeLisi and others(67), Leboyer and others (68), and Albus and Maier (69),whereas in the definitely nonfamilial cases of Albus andMaiers sample, the onset-age difference grew to 5.7 years.Evidently, the protective effect of estrogen is the more likelyto prevail, the lower the genetic liability. In addition, patientsof both sexes with a high genetic load seem to developschizophrenia at a relatively young age (69).

The lifetime risk for schizophrenia until age 60 appears tobe the same for men and women. In earlier studies in theUnited States, higher lifetime incidence rates for men pre-dominated, in part because of the age cut-off of 45 years inthe DSM-III diagnosis, in part because of the samplesrecruited from public mental hospitals with higherproportions of male patients. The use of criteria representingmore stringently defined schizophrenia (for example, dura-tion criterion in DSM-III and DSM-IV) seems to yield asignificantly more disparate male-to-female ratio (70). Ham-brecht and others (56) have recently discussed the methodo-logical pitfalls that explain the predominance of men in somestudies, for example, an underrepresentation of primarilyfemale late-onset cases.

A cumulative depiction of the incidence rates for men andwomen in 5-year age bands until age 59 from the ABC studyshows that the cumulative incidence, a good indicator of thelifetime risk as based on an ICD-9 295 diagnosis of schizo-phrenia is practically the same for both sexes at 13.2/100 000for men and 13.1/100 000 for women. Men clearly consume

Figure 2. Annual first-contact rates of nonaffective psychosis at age60+ (based on administrative data).

Figure 3. Mean age values at 5 definitions of onset until first admis-sion. First-episode sample of schizophrenia, broad defini-tion (N = 232).

March 1997 Epidemiology of Schizophrenia 145

their lifetime risk more rapidly than women do, but from age30 to 35 on, the rates for women approximate and finally meetthose for men.

Temporal Trends

Considering the even distribution of morbidity acrosscountries and cultures (see Figure 1), great variation overhistorical time is unlikely. This is a difficult assumption toverify, however, because it requires the registration and diag-nosis on a fairly identical basis of all cases from a large,statistically well-prepared population over a long period con-trolling for demographic changes.

The belief that schizophrenia did not exist before the 18thcentury (71) is extremely unlikely to be true, and so is theconviction that its incidence has increased with the bourgeon-ing population in the 19th and 20th centuries (7174). De-creases of 40% to 50% in the first-admission rates forschizophrenia from the mid-1960s to about the mid-1980swere recently reported by Munk-Jrgensen (42) from Den-mark, Eagles and Whalley (75) from Scotland, and Der (76)from England and Wales. Ders interpretation of the findingsas true morbidity trends triggered a critical debate in TheLancet and the European Archives of Psychiatry and ClinicalNeuroscience. The main point raised was that the number ofavailable hospital beds and first admissions for a few otherdiagnoses, such as affective psychoses and neurotic disorder,also fell by approximately the same amount in these countriesover the same period (77,79). Strmgren (78) and Kendell andothers (80) also pointed out that the diagnosis of schizophre-nia had become more restrictive during this period.

Warner and de Girolamo (36), referring to repeated, cross-sectional investigations with the same methodology at somestudy sites over the period in question, found stable,age-corrected rates. Only 3 longitudinal studies fulfilled therequirements mentioned for the investigation of long-termmorbidity trends in schizophrenia (17,81,82). They wereconducted on case-register data for Norway, Iceland, and thestate of Victoria, Australia. The longest period was coveredin the Australian study, in which a retrospective applicationof operationalized diagnoses to random samples of case re-cords was used. All of these studies found fairly stable rates,indicating that temporal changes in schizophrenia morbiditycurrently or in the recent past must be considered unlikely.

Clinical Epidemiology

Clinical epidemiology aims at generally valid conclusionsfrom clinical samples. The precondition is that study samplesare representative of the disorder in question or at least of adefined subtype. The diagnostic definition should not includeany course criteria, such as the 6-month criterion in DSM-IIIand DSM-IV, which is bound to lead to a biased selection inthe sample and thus to distorted results. Some epidemiologi-cal aspects of a disorder with an irregular, episodic coursealso require comparisons at an identical stage of illness toavoid confounds from different duration of illness (83). Thisrequirement has been fulfilled only recently in primarilyfirst-episode studies (43,84).Symptomatology of the First Episode across the Life Cycle

Early-onset schizophrenia (under age 21) and very early-onset schizophrenia (under age 14) are characterized by dis-organization and a high frequency of poorly differentiatedand nonspecific symptoms, severe conduct disorders, andfunctional impairment: the more prominent these symptoms,the younger the patients are at onset (85,86). The sex distri-bution of early-onset schizophrenia shows a slight predomi-nance of males in most studies, but the opposite has beendemonstrated in other studies. The studies, mostly based onfirst-contact samples at child psychiatric institutions, how-ever, usually do not include admissions after age 18. For thisreason, some young male cases of schizophrenia may bemissed because their asocial behaviour brings them into con-tact with social and youth guidance services as well as juve-nile courts before reference to mental health services (87).

Testing the conclusion drawn from several studiesthatearly-onset schizophrenias are more severe than late-onsetschizophreniasinvestigators from the ABC schizophreniastudy, on the basis of PSE and CATEGO syndrome scores(37), found that the PSE total scores were significantly lowerfor late-onset patients, men and women taken together. Asshown in Table 4, the result was accounted for to a lesserextent by the specific symptom scores DAH (delusional andhallucinatory syndromes) and BSO (behaviour and speech),and primarily by the 2 nonspecific scores SNR (specificneurotic syndromes) and NSN (nonspecific neurotic syn-dromes). The implication of this finding is that the greaterseverity of early-onset schizophrenia is primarily attributableto a higher frequency of symptoms not specific to psychosis.

A comparison of the symptom scores in early- and late-onset schizophrenia (< 21 years versus 40 years) by sexyielded different age trends for men and women. On 4 out of8 symptom dimensions, late-onset men scored significantlylower than early-onset men. For late-onset women, not asingle indicator was significantly more favourable and one,the SANS global score, was more unfavourable in late-onsetwomen (Table 5).

This means that the milder symptomatology in late-onsetschizophrenia as a whole was accounted for by men alone,while the total scores for late-onset women did not decrease,and the SANS score, measuring negative symptoms, even

Table 4. Symptomatology at first admission: CATEGO syndromescores and total score by 3 age groups (N = 232)

Onset agea in yearsSyndrome 12 to 20 21 to 35 36 to 59 ANOVADAH 11.2 10.3 10.1 P < 0.7

BSO 8.7 7.8 7.4 P < 0.4

SNR 9.6 6.7 6.6 P < 0.003

NSN 16.3 15.5 13.3 P < 0.08

Total score 45.9 40.4 37.7 P < 0.03

aOnset defined by first psychotic symptom.

146 The Canadian Journal of Psychiatry Vol 42, No 2

increased in comparison with early-onset cases. In keepingwith the estrogen hypothesis (5860,62,88), we assume thatthis finding resulted from the waning protective effect ofestrogenresponsible for the delay in onset and the milderearly symptomatology in women. In the premenopausalperiod, this would explain the higher frequency and severityof schizophrenias developed by women at this age. Theprotective effect of estrogen lacking, men develop relativelysevere cases at a young age, but relatively milder cases withgrowing age of onset.

Age and Sex Differences in Illness BehaviourA series of studies has consistently reported a higher

frequency of conduct disorders, especially asocial and crimi-nal behaviours, and of substance abuse in schizophrenic men(89). The WHO Determinants of Outcome study (2) alsofound more first admissions triggered by acts of violence inmen than in women (22.2% versus 13.9%) (56).

In the ABC schizophrenia study, comparisons by sex, agenot taken into account, did not reveal any significant differ-ences in the core symptoms. As stated by Goldberg and Gold(90) with respect to neuropsychological test results in first-episode patients, the disorder itself appears to be fairly similarin men and women. The most pronounced sex differenceemerged in behavioural items, such as self-neglect, reducedinterest in a job, social withdrawal, and deficits of communi-cation, which were all significantly more frequent in men(Table 6). The socially negative items in men showed thehighest frequency before age 25 and the lowest frequencyafter age 35.

Considering that population studies have shown conductdisorders, antisocial and violent behaviour, and substanceabuse to be significantly overrepresented in men from pubertyto early adulthood (91), it is more plausible to classify this sexdifference in schizophrenia as illness behaviour rather than asa direct expression of the illness. This presumes that thesocially negative behaviour of young males, also reflected ina deficient compliance with care provision, has an unfavour-able impact on outcome (92).

By using syndrome scores derived from the systematicArbeitsgemeinschaft fr Methodik und Dokumentation in derPsychiatrie (AMDP) symptom check list (93), the main itemsof which are identical with the PSE, we compared a large,consecutive, first-admission sample of schizophrenic patients(n = 1109) from the Mannheim-based CIMH in the years 1978to 1992 by 5-year age bands across the total age range (> 15to 75). Neither significant sex differences nor age trendswere found in any of the schizophrenic and affective syn-drome scores.

At the level of single symptoms, the majority showed onlylittle variation with age. Only very few symptoms showedhighly significant and pronounced age differences: as illus-trated in Figure 4, based on 5-year age groups from 15 to 19years until 75 to 79 years, all the percentages of cases present-ing systematic and paranoid delusions increased linearly withage across the total age-of-onset range. Systematic delusionsshowed a sixfold increase from 7% in the youngest age groupto 44% in the oldest group. Goodness of fit tests (linear logitmodel) demonstrated highly significant linear increases ordecreases in frequency in logits with age.

Unlike the delusional symptoms, the key symptoms ofincoherence of thought and disordered sense of self,indicators of the disorganizational syndrome dimension par-ticularly frequent in early-onset schizophrenia (85,87), de-creased linearly over the entire age range. These 2 trends areprobably attributable to developmental factors and, again, arenot expressions of the basic psychophysiological process ofthe disease. This means that the level of cognitive and per-sonality development at the onset of the disorder is reflectedin symptoms (85,94,95). As the increase in paranoid andsystematic delusions indicates, the cognitive and coping abili-ties of personality at more mature stages of personality devel-opment become more differentiated and increasingly stable,thus reducing the disorganizing effect of the psychosis onoverall mental functioning.

Like the socially negative illness behaviour of youngmales, the age trends in the leading positive symptoms

Table 5. Sex differences in symptom scores at time of first psychotic episodeearly versus late onseta

Men WomenSymptomatology Early (n = 28) Wilcoxon Late (n = 9) Early (n = 21) Wilcoxon Late (n = 24)DAH 12.1 0.02

a 5.7 10.0 0.95 10.5BSO 8.6 0.29 7.3 8.9 0.44 7.9SNR 10.7 0.11 7.3 8.2 0.42 7.1NSN 18.9 0.03

b 11.4 13.0 0.58 13.8Total score 50.3 0.02b 31.8 40.0 0.80 39.2SANS 9.3 0.29 6.6 6.7 0.08

c 9.5PIRS 10.7 0.26 8.4 9.8 0.73 10.5DAS-M 3.0 0.06c 1.8 1.9 0.61 1.8

aAge at first psychotic symptom < 21 years versus 40 years.bP 0.1.cP 0.05.Arrows mark the direction of the age difference.

March 1997 Epidemiology of Schizophrenia 147

Eugen Bleuler (96) regarded them as secondary symp-tomsbut not in the negative symptoms, illustrate the extentto which personality development, together with genetic andprobably also environmentally determined brain processes,influences the clinical expression and probably also thecourse of the disorder. This issue was recently raised byGaldos and van Os (97) with reference to the fact that fullyelaborated positive symptoms, such as paranoid andsystematic delusions, require a certain degree of cognitivematurity and education, for example, knowledge of the sys-tems included as explanatory principles in the delusions. Theinteraction of disease and development is likely to becomeone of the key topics for future schizophrenia research and tohelp build a bridge between genetic, epidemiological, andpersonality research.

Discussion

The epidemiology of schizophrenia is still faced with aseries of unsolved methodological problems, making conclu-sive interpretations and meaningful comparisons difficult.Among these problems are the definition of the diagnosis byconventional criteria, the variability of illness courses despitethe similarity of psychopathological symptoms, and the het-erogeneity of the study populations. The difficulties resultingfrom nonrepresentative study populations or from a failure tocheck the findings against alternative interpretations arereflected in the controversy produced by the reports of de-creasing first-admission rates for schizophrenia from the mid-1960s to the 1980s in some regions. Equally controversialissues are the similarity or difference of age at onset in menand women, the association between social class and the

morbidity risk, and the distinction of empirical subtypes ofschizophrenia.

The knowledge available allows some fairly reliable con-clusions about the epidemiology of schizophrenia, however:the average age-corrected morbidity risk for schizophrenia ofa restrictive definition is 0.1/1000 population per year, with

Table 6. Gender differences in symptomatology at first admission and during early course(ABC Schizophrenia First-Episode Sample, N = 232)

Symptom Males (%) Females (%) P(2)aCross-sectional at first admission (PSE, PIRS, SANS, DAS)

Behaviours:

Overadaptiveness/conformity 5.8 14.9 0.029

Behaviours more frequent in men:

Self-neglectDeficits of free-time activitiesDeficits of communicationReduced interest in a jobSocial disability (overall estimate)Loss of interestsDeficits in personal hygieneSocial inattentiveness

38.181.976.468.384.758.136.548.0

18.054.150.731.362.739.519.531.3

0.0010.0010.0010.0020.0020.0050.0050.012

Cumulative prevalence during early course (IRAOS)Behaviours more frequent in women:

Restlessness 79.6 92.7 0.003

Behaviours more frequent in men

Drug abuseAlcohol abuseReduced activities in free time

39.831.574.1

21.016.955.6

0.0020.0090.003

aThe table gives results only for those items (out of the total of 303 items of PSE, PIRS, SANS, DAS, and IRAOS) in which (for alpha-correction) a significant gender differencewas validated with at least a statistical trend (P < 0.10) in both randomly split subsamples.

Figure 4. Psychotic symptoms with significant age trends.

148 The Canadian Journal of Psychiatry Vol 42, No 2

a range from 0.07 to 0.14/1000. It is unlikely that cultural,social, or ecological factors play a crucial part in the etiologyof schizophrenia.

Schizophrenia is primarily a disorder of adolescents andyoung adults. The mean age at first contact with mental healthservices is 25 to 35 years for both sexes together. In three-quarters of first-episode cases, the first psychotic symptom ispreceded by a prodromal period of 6 years on average.Negative and nonspecific symptoms emerge, on average, 5years earlier than positive symptoms. Both symptom catego-ries show an exponential accumulation until the climax of thefirst episode and disappear altogether or at least partly afterthat. Irrespective of how onset is defined, women fall ill 3 to4 years later than men. The age distribution of onsets forwomen shows a second peak in those aged 40 to 45 years.Despite the difference in age of onset, the core symptoms andalmost all the other actual disease variables do not differbetween the sexes. A pronounced difference is the predomi-nance of socially negative behaviour and substance abuse inyoung male patients, but this finding very likely reflects age-and sex-specific illness behaviour and is not a direct expres-sion of the disorder.

Overall, the onset of schizophrenia is determined by vari-ous factorsgenetic and general biological (for example,estrogen)and these same factors, interacting with age- andsex-specific behaviour and level of development at onset,influence the clinical expression and social course.

Clinical Implications

Incidence rates of schizophrenia appear stable across countries,cultures, and over time.

Given a narrow definition of schizophrenia, the annual inci-dence rates vary around 1 in 10 000.

On average, women fall ill 3 to 4 years later than men, probablybecause of a protective effect of estrogen.

Limitations

Comparisons among studies are difficult because of differentialstandards in methodology.

It is still unclear whether schizophrenia-like late-onset psycho-ses should be classified as schizophrenia.

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Rsum

Objectif : Caractriser lpidmiologie de la schizophrnie.Mthode : Analyse documentaire narrative.Rsultats : Chaque anne, un adulte sur 10 000 (g entre 12 et 60 ans) est atteint de schizophrnie. Lorsquon utiliseune dfinition restrictive et prcise du diagnostic, des mthodes dvaluation normalises et des populations larges etreprsentatives, on constate que les taux dincidence semblent tre demeurs stables, dun pays et dune culture lautreainsi quau fil des ans, et ce depuis au moins 50 ans. Les malades schizophrnes ne viennent pas au monde socialementdfavoriss, ni dfavoriss quant leur milieu. La rpartition ingale des taux de prvalence est le rsultat de la slectionsociale : lapparition prcoce de la maladie mne une stagnation sociale alors quune apparition tardive entrane unediminution du statut social. La principale zone dge, pour ce qui est des risques de schizophrnie, se situe entre 20 et35 ans. On ne sait pas encore si les psychoses dallure schizophrnique dbut tardif (comme les paraphrnies tardives),qui se dclarent aprs lge de 60 ans, devraient tre classes comme des schizophrnies, que ce soit au planpsychopathologique ou tiologique.Dans 75 % des cas, la premire hospitalisation est prcde dune phase prodromique dune dure moyenne de 5 anset dune prphase psychotique dun an. Chez les femmes, la maladie se manifeste gnralement 3 ou 4 ans plus tard quechez les hommes et une deuxime priode dapparition leve concide peu prs avec la mnopause. Les schizophrnies dbut tardif sont donc plus frquentes et plus graves chez les femmes que chez les hommes. Les diffrences entre lessexes quant lge dapparition de la maladie sont moindres lorsque le fardeau gntique est lev et elles sont plusgrandes lorsque le fardeau gntique est faible. Le mode dapparition et les principaux symptmes de la maladie sontsimilaires chez les deux sexes. Les diffrences les plus marques entre les sexes se situent au niveau du comportementsocialement ngatif d la maladie, qui est observ chez les jeunes hommes.Conclusions : Parmi les facteurs qui dterminent lvolution sociale et lissue figurent le niveau de dveloppement socialau moment de lapparition de la maladie, le trouble lui-mme (par exemple le fardeau gntique, la gravit dessymptmes et les dficits fonctionnels), les facteurs biologiques gnraux (par exemple, loestrogne) et les comporte-ments pathologiques spcifiques au sexe et lge.

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AbstractClinical ImplicationsLimitationsReferencesRsumTablesTable1Table 2Table 3Table 4Table 5Table 6

FiguresFigure 1Figure 2Figure 3Figure 4