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H H?§fner, K Maurer, W L??ffler and A Riecher-R??ssler
The influence of age and sex on the onset and early course of
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British Journal of Psychiatry (1993), 162, 80â€”86
Since Kraepelin's (1909â€”15) and E. Bleuler's (1911)
pioneering work on schizophrenia, age effects on the
onset of the disease have mostly been studied in
childhoodand old age. The younger the onset of
childhood psychoses, the more difficult they are to
(Ruuereta!, 1967; Kolvin
1973;Remschmidt eta!, 1991).This is not specific to
schizophrenia, but is due to the limited differentiation
of cerebral and mental functioning in childhood.
Late-onset schizophrenia, beyond the age of 40,
has been explored more thoroughly.
Harris & Jeste's (1988) review of 30 European
studies, late-onset schizophrenia is characterised by
hearing loss and ocular
chronicity. Beyond question is the predominance of
women in late-onset schizophrenia.
ratio of first admissions beyond the age of 40 was
1: 1.9 in M. Bleuler's study (1943) and 1: 1.8 in
Huber et al's (1979). Unlike age at onset, the
cumulative risk for schizophrenia seems to be equal
in males and females up to the age of 60 years
(HÃ¤fner et a!, 1989, 1991c).
The present study of the onset and early and later
course of schizophrenia examined whether the sex
difference in age at first admission is accounted for
by a sex difference in age at onset, and whether the
symptoms and early course of schizophrenia differ
between the sexes.
The male: female
Since no fully operationalised
of the first appearance
or remission in the early course of the disease had been
interviewfor the retrospectiveassessment of the onset of
schizophrenia â€”¿? the IRAOS (HÃ¤fner eta!, 1990, 1992)- on
the basis of a selection of internationally approved
instruments (e.g. those of Wing eta!,
Organization,1978a, 1988; Andreasen,
Longer eta!, 1985). For onset assessed in periods extending
fromone yearto threemonthsbeforeinterview,inter-rater
reliability(kappa) rangedfrom 0.62 to 1.00, and pairwise
agreement was between 73%
notes and other objective data were analysed.
All interviews were performed
or psychologists. The first interview, focusing on the
measurement of psychopathology,
Examination (PSE; Wing et a!, 1974), took place within
two weeksof firstadmission. The second interview,using
the IRAOS, was usually conducted after the episode had
remitted. Sincethe whole procedure, including the gauging
of lifeevents,copingassets,and socialsupport resources,
took sixto sevenhours, thepatientshad to beinterviewed
on several occasions, and some after discharge.
Thepatientshad beenadmittedto any of theten mental
hospitals and units in a large catchment
1.5 million â€”¿?to avoidsocial,
due to too small a population at riskâ€”¿?
(1987â€”89). Furtherinclusioncriteriaat firstadmissionwere:
method of assessing the point
of symptoms and their accumulation
1973; World Health
using the Present State
area of population
sex- or age-related selection
over two years
(a) German citizenship
(b) age between 12 and 59 years
The Influence of Age and Sex on the Onset
and Early Course
HEINZHAFNER,KURT MAURER,WALTERLOFFLERand ANITA RIECHER-ROSSLER
A new standardised interview for the retrospective assessment of onset and early course
of schizophrenia(IRAOS)was usedto studythe influenceof age andsex on time of onset
and psychopathologybeforefirst admissionin 267 schizophrenicpatientsadmittedfor the
first time. Mean age at onset, accordingto variousoperationaliseddefinitions,differedby
threeto four yearsbetweenthe sexes.Theagedistribution atthe earliestsignof mentaldisorder
showedanearlyandsteepincreaseuntilthe ageof 25 in males,anda delayedandsmaller
increasein females, with a secondpeakin women aged45â€”79. Schizophreniabeganwith
negativesymptomsin 70% of cases,appearingtwo to sixyearsbeforeadmission,andall
positivesymptomsappearingupto two yearsbefore.Bothpositiveandnegativesymptoms
accumulatedexponentially.The earlycourseof the diseasewas similaracrossagegroups,
exceptthere was a longerperiodof negativesymptomsbeforefirst admissionin late-onset
schizophrenia inwomen. Thefew significantagedifferencesinsymptomswere presumably
dueto generalage-dependentreactionpatternslikeanxietyanddepressionorthe cognitive
development of personality, asindicated by an increasein fully elaboratedpositive symptoms,
297, 298.3, 298.45814.81910.23919.01:
1 (complete PSEandIRAOSinterviews)267100.0127100.0140100.01:
297, 298.3, 298.43312.41411.01913.61:
2 (complete PSEinterviews only)276100.0133100.0143100.01:
AGE, SEX, ONSET AND COURSE IN SCHIZOPHRENIA
(c) residence in the semiurban catchment area, that
is, the cities of Mannheim and Heidelberg, the
Rhine-Neckar District and the Eastern Palatinate
(located in the central part of western Germany)
(d) first clinical diagnosis of schizophrenia(or related,
not lifelongdisorders)(ICD-9 codes295,297,298.3,
298.4 (World Health Organization, 1978b)) (the
ourtransnational case-register studyonsexdifferences
in age at onset in schizophrenia (HÃ¤fner et a!,
1989)) absence of organic psychosis and severe
had been investigatedin
This age range was chosen because beyond it diagnoses are
unreliableand numbersof caseslow.
Onset was defmed
(a) first signof mental disorder (specificor non-specific)
(b) first psychotic symptom (specific)
(c) index episode (leading to hospital admission) and
(d) first hospital admission for a diagnosis of schizo
each patient ledto a high non-inclusionrate. Of the 392
or weremissedbecauseof shorthospitalstays.Inthecase
of nine further patients, onlythe PSE interview,but not
for all patients. Amongthe patientsomitted, therewasa
slightlylowerproportionof the morerestrictivediagnosis,
lCD 295(78.4% v. 88.0% for subsample2), andtheywere
slightly older at first admission (32.9 years v. 30.5 years
for thosecompletingboth interviews).The inclusionof the
missed cases would have increased the significant sex
difference in age at first admission from 3.9 to 4.5 years.
The only remarkable sex difference was found in the
32.3Â°lo of the females versus 9.3% of the males had an lCD
diagnosisof 297, 298.3 or 298.4. Thisdifferenceexplained
the slightlysmallerproportion (13.6%)of femaleswitha
and IRAOS interview)compared with the corresponding
figureforthetotal sample(19Â¾) (Table1).Thereciprocal
difference of a larger, but non-significantly elevated
proportion of clinical diagnoses of lCD 295 in males
(89.5%v. 86.7% in females)and a larger proportion of
operationalisedlCD 295and S+ (cAmoo) diagnosesin
females(79.0% and 74.1% v. 72.9% and 66.9% in males)
in subsample2 (those withcomplete PSE interviewsonly)
cannot be explained by the slight predominance
diagnoses'amongthe femalesomitted. Behindit probably
liesa greaterreadinessto applythe restrictivediagnosis to
malepatients(Munk-JÃ¸rgensen, 1986)owingto theirmore
SexdifferencesIn age at onset
To test the reliability of the patients' statements about their
been followed by a family member from the beginning and
for whom there were objective data available. The mean
ages at onset, based on the patients' and their relatives'
statementsand the researchpsychiatrists'assessments,are
given in Table 2.
of mental disorder. The only marked, although non
significant, difference emerged with the first psychotic
in the case records some 12 months later than perceived
by the patients. As these symptoms are subjectively
experienced(e.g. hallucinations)and are not necessarily
perceivableby others, the time lag betweenthe patients'
statementsand those of the relativesand the case records
InFig. 1thedistributionsof thethreedefinitionsof onset
across the age range of 12â€”59 years are based on the
Total sample and subsamples by sex and diagnosis
assessment of onset28.128.427.80.25Beginning
of index episode29.429.029.40.61First
second increase occurred, with a peak in those aged 45â€”
The second peak was also observed with female first
value from the steady decline after the first peak, the actual
percentage first admitted aged 45-54 years was significantly
higher(P@0.05). There wasalso a significantdifference
between the percentage of male and female first admissions
beyond the age of44: in subsample 2, 3.6% ofthe males, but
9.1Â°!. of thefemales,werefirstadmittedforschizophrenia
beyond this age threshold (P@0.0l).
Themeanagedifferencesfor three definitionsof onset
were3.2 years(first signofmental disorder;P@0.05), 4.1
years (first psychoticsymptom;
(first admission; P@0.00l).
milestonesindicates the similarity
schizophrenia in males and females,
differencein age at onset.
In viewof the equal lifetimerisk of schizophreniafor
males and females up to the age of 59 years, the older age
at onset in femalesand the distribution of onsets across
the female life cycle, we assumed that vulnerabilityto
towards menopause. In German
starts to be irregular at a mean of 45 years and stops at
leastfor oneyearat a meanageof 50â€”51 years.That both
ages fall within the age range for the second peak of onsets
in women may support the oestrogen
cause of schizophrenia (Loranger, 1984; Seeman, 1986;
HÃ¤fner, 1987; Lewine, 1988). We have tested the assumption
of a neuromodulatory effect of oestradiol on dopamine
induced behaviour and on D2 receptor
animal model and the association
and symptom intensity during the menstrual cycle in a
clinical study. The results have been published
(HÃ¤fner et a!, 199la).
with the expected
The parallelism in these
of the early course
and 3.9 years
of the sex
levels between oestrogen
The Influenceof age and sex on symptomsand course
The IRAOS allowed us to assess deficits in social
functioning,neurotic and affective
positive and negative symptoms. The following analysisis
based on the 13 negative symptoms and 17 positive symptoms
included in the IRAOS (negativeâ€”¿?
social withdrawal (suspiciousness),
loss of libido, increased distractability,
intentionalthinking, disturbanceof affect, disturbanceof
speech, lack of self-care, underactivity, slowness, social
withdrawal (communication), loss of interest; positive â€”¿?
thought disorders,thought insertion,
thought echo, thought block or withdrawal, auditory
other hallucinations, delusions of control, delusions of
reference, delusions of persecution, expansive delusions,
delusions of influence,primary
concerning appearance, other delusions).
An attempt was made to determine the exact time at
which each symptom first appeared.
impossible,an estimate was made.
For the 236 patients reporting to have had positive
and negative symptoms before first admission, the mean
symptoms,as well as
anergia and retardation,
Where this was
an almost parallel shift towards younger age in the male
and femaleagedistributionswhenonsetisdefinedas first
psychoticsymptomor firstsignof mentaldisorder.Of the
males41%, butof the females
admittedfor schizophreniabefore the age of 25, while 62%
of the males, but only 47% of the females, had the first
sign of mental disorder before 25 years.
Among males, the distribution
of onset showed an early, steep increase- as we had
already shown on the transnational case-registerdata
from Denmarkand Mannheim(HÃ¤fner eta!, 1989)- with
a pronounced peak in those aged 15-25 years, followed
by a steadydecline,whereasamong femalesthe increase
was later and peaked in those aged 20â€”29 years. As in
the case of males, a continuous decline followed, but a
only 25Â¾, werefirst
for the earliest definition
12-14 15-1920-24 25-29 30-3435-3940.44 45.49 50-54 55.59
15-19 20-24 25-29 30-3435-3940.44 45-49 50-54 56-59
Fig 1 Distribution ofageatonset(asÂ¾ ofwholesample) ofschizo
phrenia (broad definition, ICD-9 295, 297, 298.3, 298.4). (a) Males
(.... earliest sign of mental disturbance, n= 117;â€” first psychotic
symptom,n= 125;â€”¿? indexadmission, n= 133).(b)Females(
earliestsignof mentaldisturbance,n= 131;------first psychotic
symptom,n= 139;â€”¿? indexadmission,n= 143).Source:HSfner
et a! (l99lb).
number of continuously present positive and negative
symptoms per monthwas calculated.
presentedalong a time axisextendinga maximumof 15
years back from first admissionin Fig. 2.
There is an exponentialincreasein both positiveand
negativesymptomsup to first admission(Fig. 2(a)). In
some cases, negativesymptomsstartedto appear 15years
in the second-lastyear, and againin the last year before
first admission. Positive symptoms began up to 10years
15 1413 -12-11 -10-5 -5.744 -4 .3-2-1
â€¢¿?5-184.108.40.206I.Io.g4 -7444 -3 -2-1
AGE,SEX, ONSETAND COURSE IN SCHIZOPHRENIA
before first admissionand doubled in the followingfive
years,and again in eachof the
periods. In the yearpreceding firstadmission, they increased
of the indexepisode.
To investigateage differencesin initial symptomsand
size:12â€”24 years(47males,33females),25â€”34 years(43
The course of positive and negative symptoms hardly
differed betweenthe three age groups (Fig. 2(b)). The
fmdingthat positiveand negative
last yearsymptomsstarted to
atrivialageeffect,becauseinmanycasesthe 15-year period
somewhatlater amongthose under25yearswas
/,analysed extendedto childhood. Thelikelihood ofchronic
theoldest group,butno differences
this and the intermediategroup. The number of positive
equal in thefewmonths preceding
beforefirst admissionwas naturallygreatestin
,,@2 / wereobserved between
o firstadmission,as was
120 truewhenmales and femaleswere compared.
A comparison of the early course of positive and negative
that there were no essential differences between the
intermediate group (25-34 years) and the total group. When
the youngest group was contrasted
between malesandfemalesby agegroup showed
/ with the oldest (Fig. 2(c)
2 @./ v. 2(d)), reverse patterns ofcourseemerged for malesand
In the youngest group,negative symptomsstarted
12440 years beforefirstadmission. Positivesymptomsstarted to
women who first showeda similar increasein negative
symptomseight years, but males aslate asfour years, before
group lSStyw,in femalesthe oldest it was
2 ,@..-â€˜/// firstadmission.Thesex difference culminatedone year
....@/beforefirst admission, anddisappeared subsequently.
These results throw doubt upon two classic assumptions
implications(e.g. Murrayeta!, 1985;Lewine, 1988;Castle
& Murray, 1991);(a) that negative symptoms and an
insidiousonsettend to be considerablymore frequentin
schizophrenia recentlydiscussed with newtheoretical
Interactionsbetween age, sex,
aremorefrequent, and negativesymptoms less
o andnegative and positive
(a) betweenpositiveand negativesymptoms
This findingindicatesthat the two syndromesare closely
associated at the early stage of the disease and suggests that
theymightat leastpartlybeof a commonorigin(Hllfner
& Maurer, 1991;Maurer & Hllfner, 1991).
(b) betweensexand age at onset
This relationship, which persists over the life span, is
reflected in the significantsex difference
weretested by meansofa log-linearmodel and
in the mean age
-15-14-13-12-11-10-54 .74-6-4 -32 -1
-15-14-13-12.11.104-5.74 -6 -4 .3 -2â€¢¿?1
until first hospital admission
with positive or negative symptoms present before onset. (a) For
males and females (â€” negative, male; -
Cumulativenumbersof positive and negative
among 236 patients
â€”¿?positivemale; .... positive,female).(b)By agegroup
25-34; â€”¿? negative,agegroup 35-59',â€”¿? positive,agegroup 12-24;
positive, age group 25...34,
(C) Age group12â€”24 years(â€”negative,
female; â€”¿?positive,male; ....
35â€”59(â€” negative, male; - - - - negative, female;â€”¿? positive,
male; ...positive,female).Source: Ht.fner eta!(1991c).
pocgive, age group 35â€”59).
positive, female). (d) Age group
Delusions of persecution43.057.968.7â€œSANS
(c) between the development
age of onset.
This is accounted for by a slightly increasing proportion
of negative symptoms persisting
before first admissionwithincreasingage. No significant
relationship was observed between the developmentof
positive symptomsand age of onset. Nor could we find any
of negative symptomsand
formorethan one year
Cross-sectional agedifferences insymptoms atfirstadndmlon
In our total PSE interview sample, of 276 patients, the
proportions of patientswitha CATEGO diagnosisbasedon
lCD 295 or the proportion of patients receiving a CATEGO
class S + at first admissiondid not differ
correlation between age and the four CATEGO subscores
rangedfrom â€”¿? 0.10 to 0.00; the correlation
and the CATEGO total score was also slight (r= â€”¿?
bytheCATEGO program,few andsmalldifferencesbetween
the threeage groupsemerged.Significantdifferenceswere
found with six syndromes only (Table 3). While delusions of
of reference were most frequent in the intermediate age
group; non-specific syndromes, such as situational anxiety,
slowness, were most common in the youngest group. To
see whether these age differences
differences, the percentages of positive ratings of the
compared between males and females. No significant
differences between the sexes were obtained.
Overall, the negative symptoms differed little between
the agegroups. Sexdifferenceswerefound withtwo of the
four items of the Scale for Assessment of Negative
Symptoms (SANS; Andreasen, 1982)showing significant
peers were more frequent in males than in females in all age
with age. The
were mediated by sex
significantly with agewere
groups - the differenceattaining significancein the youngest
grouponly- but thepositiveratingsof thisitemincreased
significantlywithagein both malesand females.Onlythe age
difference in the SANS global rating â€˜¿?anhedonia/asociality',
whichwas found with three-quartersof the schizophrenic
males in each age group, was entirely accounted for by
females,among whom this rating
in the youngest group to 83.0Â¾in the oldest.
hallucinations and three items of delusion were most
frequencyof positive symptoms in this age group. When
onset was later,paranoidsymptomsincreased- theclassic
delusion of persecution from 44% in the youngest group
to morethan70Â¾ intheoldest- andso, althoughto alesser
extent, did affective conditions possibly related with
have an age distribution similar to that in the total
population. Anxietystates wereby farmost frequent inthe
youngest group. Two depressive symptoms, delusions of guilt
reacheda maximum in the intermediate group.Unlike
delusions of persecution,non-specific
such as simple delusions or delusional depersonalisation,
werealso most frequent in the youngestgroup.
Negative symptoms appeared to beless dependent
Apart from sex differences, they were encountered
admission at almost equal frequencies in all age groups.
Again, sexdifferencesdidnot explaintheseagedifferences.
increased from 38.2Â°Io
The sex difference in the mean age at first admission
for schizophrenia is apparently almost or completely
accounted for by a sex differencein age at onset.
age differences: CATEGOsyndromesand SANS itemswith significantpercentages of positiveratings per age group
a positive rating
group 12-24 years(n=90)
Substance abuse Drugabuse
Avoidance of provoking
Delusions of guilt35.9
Irritability (not hostile)67.5Negative
Delusions of reference
group35-59 years(n= 76)
(paranoid) persecution70.4(Paranoid?) Delusions of
Incongruity of affect
Povertyof contentof speech28.7Negative
HSfner eta! (1991c).
AGE, SEX, ONSET AND COURSE IN SCHIZOPHRENIA
PSE items showing significant differences between age
groups, listed according to age-group maximum
of positive and for the most part also of negative
symptoms. The differences
be explained by general age-dependent
influencing non-specific aspects of psychopathology,
disease behaviour, and the content or cognitive
structure of several positive symptoms.
slight accumulation of anxiety symptoms
lescence and of individual depressive symptoms in
the intermediate group (25â€”34 years) only reflects
the age distribution of anxiety and depressive
disorders in the general
1990).The tendency for non-specific, undifferentiated
delusions in adolescence, similar to those of childhood
schizophrenia, and for systematised delusions of
persecution in late adulthood,
contribution of cognitive development towards more
elaborated symptoms or towards more rational
and projective coping with the pathological experi
accumulation of paranoid delusions
older age. It is reflected in a rapid increase in non
schizophrenicparanoid disorders of multifarious
origin with age.
The early course of positive and negative symptoms
in the years preceding first admission for the index
clear-cut sex differences. Only a comparison between
the males and females of the youngest and the oldest
group produced a remarkable
frequencyof negative symptoms
extended course in women over 35. This contradicts
the theory that late-onset schizophrenia
disease involving fewer negative symptoms in women
than in men. It is compatible with Harris & Jeste's
(1988)conclusion of a tendency to chronicity in late
psychopathology of schizophrenia in women whose
onset is probably delayed by a hormonally reduced
vulnerability up to menopause (Hafner eta!, l991a)-
comparable to the effect of neuroleptic maintenance
medication - does not essentially differ from schizo
phrenia developed earlier in life.
In all age groups the epidemiological picture of
schizophrenia at onset seems to be that of a fairly
uniform pattern of response of the brain to several
mostly unknown causes, the only substantial factor
influenced by sex being age of onset.
observed can partly
population (Burkeet a!,
might reflect the
of the disease.
is specific to
finding: a higher
and their more
is a milder
The investigation â€œ¿?Gender
tology and course of schizophreniaâ€• was conducted
the Central Institute of Mental Health, Mannheim, and supported
by the Deutsche Forschungsgemeinschaft
differences in age at onset, symptoma
(Special Research Branch) 258 at
later than males irrespective
defined as first hospital admission, first appearance of
a psychotic symptom, or first sign of mental disorder.
Because of the correlation between age of onset
and sex, the association
explanation of sex differences
these differencesmight just be mediated by differences
in age of onset. It was therefore necessary to clarify
whether there are also age-independent
in symptoms or the early development of schizo
Sex has a strong influence on the age distribution
at onset. Among females there is a delayed increase
in incidence of schizophrenia in adolescence and a
lower peak of onset beyond the age of 45.
Our results show that neither sex nor age at onset
has a large effect upon the core symptoms of
schizophrenia, nor do they influence the early course
fell ill with schizophrenia threeto four years
onset was of whether
between age and the
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