Gender Differences in Schizophrenia: Hormonal Effect … · nia, on average, show better pre-morbid functioning, later onset, and a more benign course of ill-ness. They are also more

VOL. 21, NO. 1, 1995 Gender Differences inSchizophrenia: HormonalEffect or Subtypes?by David J. Castle, Kathryn Abel, Noriyoshi Takei,and Robin M. Murray

At Issue The At Issue section of theSchizophrenia Bulletin containsviewpoints and arguments on contro-versial issues. Articles published inthis section may not meet the stricteditorial and scientific standards thatare applied to major articles in theBulletin. In addition, the viewpointsexpressed in the following articles donot necessarily represent those of thestaff or the Editorial Advisory Boardof the Bulletin.—The Editors.

Abstract

Compared with their male coun-terparts, females with schizophre-nia, on average, show better pre-morbid functioning, later onset,and a more benign course of ill-ness. They are also more likelyto have a family history ofschizophrenia and/or affective ill-ness, to exhibit "atypical" andaffective features, and to show aseasonal pattern of hospital ad-mission that mimics that of pa-tients with mania. However,there exists a paradox. Althoughschizophrenia in females hasmuch in common with affectivedisorder, the "schizophrenogenic"effect of maternal influenza alsoappears to be more significant infemale than in male schizophre-nia. Perhaps females with a pre-disposition to affective psychosiswho have also been subject tothe effects of maternal viral in-fection during gestation developsome subtle neurodevelopmentaldamage that renders their psy-chosis schizophrenia-like.

Schizophrenia Bulletin, 21(1):1-12, 1995.

Schizophrenia has a later onset infemales than in males; the dif-ference has been found to be

about 5 years in most studies (seeLewine 1988). The sex differencein age at onset is consistent acrosscultures (Hambrecht et al. 1992)and is robust to definition of"onset" (Loranger 1984; Riecher etal. 1989; Hafner et al. 1991) aswell as to definition of illness(Loranger 1984; Shimizu et al.1988). Furthermore, the age-at-onset distribution curves forschizophrenia differ betweenwomen and men. In a study of392 consecutive first admissionsfrom a defined catchment areawith a diagnosis of schizophreniaor paranoid disorder (the ABCstudy), Hafner and colleagues(1991) found that males showed asingle marked peak in their earlytwenties, while for females therewas a second peak of onset in the45-54-year age group. This findingis echoed in the distribution ofpooled data from the WorldHealth Organization Determinantsof Outcome study (Hambrecht etal. 1992). We (Castle et al. 1993)recently investigated gender dif-ferences in a catchment-area sam-ple of 470 patients with schizo-phrenia across all ages and foundthat a surprisingly large number(n = 134, 28%) had an onset of ill-ness after age 45 and even afterage 60 (n = 56, 12%). Males had adramatic early peak followed by amonotonous decline; femalesshowed a second peak in the lateforties and an even more emphaticpeak in very old age.

Thus, not only do females havea later mean age at onset of ill-ness than males, but the age-at-onset distribution curves forfemales and males are very dif-

Reprint requests should be sent toProf. R.M. Murray, Institute of Psychi-atry, De Crespigny Park, London SE58AF, United Kingdom.

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SCHIZOPHRENIA BULLETIN

ferent in shape. This has profoundimplications for any theory aimedat explaining gender differences inschizophrenia (see Castle and Mur-ray 1993). One possibility is thatsome factor(s) associated withbeing female serves to delay theonset of the illness. The factor at-tracting the most attention hasbeen estrogen; it has been pro-posed that during the reproductiveyears women are protected by theantidopaminergic action ofestrogens and that the slight peakin the incidence of schizophreniaamong women in the 46-55-yearage range is the result of the re-moval of this protection at meno-pause (see Hafner et al. 1991;Riecher-Rossler and Hafner 1993).An alternative explanation is thatthe gender differences in age atonset are a clue to subtypes ofschizophrenia to which womenand men are differentially prone(see Goldstein et al. 1990b; Castleand Murray 1991; Murray et al.1992). This article will addresseach of these possibilities in turn.

The Estrogen Hypothesis

Animal studies have shown thatboth D, (Hruska and Novak 1988)and D2 (Di Paolo et al. 1979,1982a, 1982b, 1984) dopamine re-ceptor numbers increase in re-sponse to estrogen treatment,specifically in the lateral caudate-putamen. This effect is seen onlyafter chronic estrogen treatment; incontrast, acute estradiol exposurerapidly converts striatal D2 recep-tors from high- into low-affinitystates (Levesque and Di Paolo1988). Estrogen affects not onlydopamine systems but also nor-adrenergic (Johnson et al. 1985),serotonergic (Fischette et al. 1983),and gamma-amino-butyric acid

(GABA)-ergic (O'Connor et al.1988) neurons in a region- andsex-specific manner (McEwen1991).

Despite the complexity of the in-fluence of estrogen on neuro-transmitter systems, the notion thatestrogen effects can go some waytoward explaining gender dif-ferences in schizophrenia hasgained currency (see Riecher-Rossler and Hafner 1993). But isthere clinical evidence of any rela-tionship between estrogen levelsand psychosis? Admission rates topsychiatric hospitals increase forwomen in the paramenstruum(Janowsky et al. 1969; Abramowitzet al. 1982; Dalton 1982; Blu-menthal and Nadelson 1988). See-man and Lang (1990) proposedthat low estrogen levels at thistime could precipitate relapse of aschizophrenic illness. However,most studies in this area focusedon affective disorders (see Ascher-Svanum and Miller 1990) or in-cluded nonpsychotic illnesses, didnot employ operational diagnosticcriteria, and did not control fortime point in the cycle. Also, casereports (Endo et al. 1978; Glickand Steward 1980; Berlin et al.1985; Brockington et al. 1988;Gerada and Reveley 1989) associ-ating psychosis and the premen-struum all describe affective psy-choses, and none of these studiescorrelated plasma hormone levelswith onset of psychotic illness. In-deed, Targum et al. (1991) suggestthat the only conclusion that canbe drawn is that the menstrualphase may be a nonspecificstressor in mental illness.

Although it is well establishedthat the puerperal period (90 dayspostpartum) is a particularly vul-nerable period for psychotic illness,the increased risk is due mostly toaffective psychoses. Thus, Kendell

et al. (1987) estimated that womenwith a past history of schizophre-nia have only a 3.4 percent risk ofpsychiatric admission postpartum,compared with a risk of 13.3 per-cent in women with a previoushistory of unipolar depression and21.4 percent in those with a his-tory of bipolar affective disorder.Pregnancy and the puerperium in-volve many steroid and peptidehormone changes apart from thesimple rise and fall of estrogens; itis likely that puerperal mental dis-orders result from a complicatedinterplay of these changes, alongwith factors involved in the socialdisruption that childbirth inevitablybrings.

The notion that low estrogenlevels postpartum increase the riskof schizophrenic relapse goes handin hand with the idea that highestrogen levels during pregnancyare protective. However, McNeil etal. (1984a, 1984b) found an overallworsening of mental health duringpregnancy, which was especiallymarked in women with schizo-phrenia; the results of Krener etal. (1989) are congruent with thisfinding.

Seeman and Lang (1990) positedthat at puberty "... the sudden,dramatic hormonal and neuro-chemical change is a risk periodfor the development of schizophre-nia, which in females is madesafer by the protective effects ofestrogen" (p. 188). However, themean age for developing schizo-phrenia is the late twenties toearly thirties in women and theearly to midtwenties in men,whereas puberty occurs consider-ably earlier (Grumbach et al. 1974).Furthermore, if estrogens are pro-tective against a pathogenic over-activity of dopamine systems, thenwomen ought to be similarly pro-tected from mania, which is also



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associated with increaseddopamine activity (Ashcroft et al.1972); however, they are not.

The menopause has long beenthought to be associated with anincrease in psychological morbidity,particularly affective disturbance(see Ballinger 1990). As notedearlier, Hafner and colleagues(1991) reported a small peak inthe incidence of schizophrenia inwomen between the ages of 45and 54 and a relative decline inmale incidence at this age. Theyattributed this peak to a fall inestrogen levels in women at thistime. However, this conclusion ispurely inferential, and there wereno data on subjects' menstrual sta-tus at the time of psychotic break-down. Few studies have attemptedto correlate the menopause withonset of psychosis, and those thathave done so have found no con-nection between admission forbroad diagnostic groups, includingschizophrenia, and recent meno-pause (Tait et al. 1957; Smith1971). Molnar et al. (1988) foundlow estrogen levels only in thosemenopausal psychotic patients withdepressive illnesses. The WorldHealth Organization (1981) con-cluded that no psychologicalsymptoms could be convincinglyattributed to a lack of estrogen;treatment studies using estrogenshave attested to this opinion(Montgomery and Studd 1991;Schmidt and Rubinow 1991). In-deed, it has been suggested (e.g.,Greene and Cooke 1980;MacKinlay et al. 1987) that sociallife events that coincide withmenopause play a greater role inpsychiatric disturbance at this timethan do biological factors.

As far as we know, the onlystudies set up to test the hypothe-sis directly are those of Hafnerand colleagues. In rats, Hafner et

al. (1991) showed that estradiol re-duced behavioral changes inducedby both haloperidol and apomor-phine and caused a reduction indopamine receptor affinity for sul-piride. Interestingly, these effectswere most marked in neonatalrather than adult rats, and theauthors concede that estrogeniceffects on brain maturation may bewhat is most important.

We consider that this hypothesismerits active investigation, as doesthe role of estrogens in brain de-generation. Rather than estrogenshaving a protective role, it couldbe that estrogen withdrawal hasadverse effects on the postmeno-pausal female brain, in, for exam-ple, accelerating age-relatedchanges in the medial temporallobe (Murphy 1994).

Male-Predominant "DementiaPraecox" Subtype

We have proposed elsewhere(Castle and Murray 1991; Murrayet al. 1992) that males and femalesare differentially susceptible to atleast two different forms of schizo-phrenia and that the excess ofmales among early-onset schizo-phrenia patients is a reflection of amale propensity to a severe early-onset form of the illness that isakin to Kraepelin's (1896) originalconception of "dementia praecox"and a consequence of neurodevel-opmental deviance. In support ofthis hypothesis, we cited evidenceof a tendency to worse premorbidfunctioning (e.g., Zigler and Levine1973; Klorman et al. 1977; Zigler etal. 1977; Lewine 1981; Childersand Harding 1990; Foerster et al.1991; Castle et al. 1993) and lowerpremorbid IQ and poor schoolperformance (Offord 1974; re-viewed by Aylward et al. 1984)

among males than females whosubsequently develop schizophre-nia. Obviously, the protective effectof a pubertal estrogen surge infemales could not explain thesechildhood differences.

We also cited evidence of morestructural brain abnormalities inmale schizophrenia patients thanin their female counterparts; wefound 10 studies (6 computedtomography and 4 magnetic reso-nance imaging) pointing in this di-rection. Flaum et al. (1990) re-viewed neuroimaging studies ofindividuals with schizophrenia inwhich gender effects were re-ported; most had small samplesizes and lacked statistical power,but males had larger ventricle-to-brain ratios than females in five ofthe six studies that found a gen-der effect. In three of their ownfour studies, Flaum et al. (1990)found that males had significantlylarger ventricles than control sub-jects but that there was no sucheffect for females. Andreasen et al.(1993) have shown that in male,but not female, schizophrenia pa-tients, the normal positive correla-tion between IQ and the volumeof various brain structures (e.g.,the temporal lobe) is lost, implyinggreater abnormality in male thanfemale schizophrenia patients. Notall neuroimaging studies of schiz-ophrenia patients have foundsuch a gender difference (e.g.,Nasrallah et al. 1990; Gur et al.1991), and studies have not beendesigned specifically to addressthis issue; however, the weight ofevidence suggests more brain vol-ume decrements in males thanfemales with schizophrenia.

Johnstone et al. (1994) recentlycarried out a most interesting re-analysis of post-mortem data onschizophrenia patients for whomthere was extensive clinical infor-



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mation. There appeared to be twoneuropathologic types. In the first,decreased brain size was associ-ated with poor premorbid func-tion, limited academic achievement,prominent negative symptoms, andpoor cognitive functions. This pat-tern is very suggestive of neuro-developmental impairment.

The second type was more com-mon in women and was associatednot with small brains or impairedpremorbid function but rather withgliosis and focal brain damage.Johnstone's work raises the ques-tion of whether such features area consequence of acquired braindamage separate from those proc-esses that cause small brain size.

Other characteristics of schizo-phrenia in males, such as morenegative symptoms (reviewed byBardenstein and McGlashan 1990)and generally worse outcome (forreviews, see Seeman 1986; Gold-stein 1988; Angermeyer et al. 1989,1990), are compatible with the no-tion that males are more prone toa severe neurodevelopmental formof the illness (see table 1). Inetiological terms, males withschizophrenia, expressly those withan early onset of illness, appearmore likely than females to have ahistory of those obstetric complica-tions implicated in the etiology ofthe condition (see Lewis et al.1989; Castle and Murray 1991;O'Callaghan et al. 1992).

Kirov et al. (submitted for pub-lication) have reviewed the evi-dence that schizophrenia patientswith a history of obstetric com-plications have an earlier onsetthan those without such a history,and the authors suggest that thisfact, together with the greater fre-quency of such histories in malesthan in females with schizophre-nia, may explain the earlier onsetof schizophrenia in male patients.

Table 1. Gender differences in schizophrenia

Males Females

Age-at-onsetdistribution

Symptomatology

Season of admission

Premorbid functioning

Neuropathology

Course of illness

Early peak with uniformdecline

More likely to exhibit"typical" and "nega-tive" symptoms

No clear seasonalpattern

More likely to showpoor premorbid socialand occupationalfunctioning and lowpremorbid IQ

More likely to exhibitstructural brainchanges

Tends to be worse interms of hospitaliza-tion and social andoccupationalfunctioning

More even distributionthroughout adult life

More likely to exhibit"atypical" and affec-tive symptoms

Cyclical pattern asmania

Less likely to havebeen socially, occupa-tionally, or intel-lectually compromised

Less likely to exhibitstructural brainchanges

Treatment, social, andoccupational out-comes are generallybetter

Kirov et al. studied 73 schizophre-nia patients diagnosed according toDSM-HI-R (American PsychiatricAssociation 1987) criteria andfound that the mean age at onsetwas, as expected, significantly ear-lier in males. However, once thosepatients (predominantly males)who had a history of obstetriccomplications were removed fromthe study, the remaining malesand females showed no differencein age at onset of psychosis.

An excess of males is a featureof other neurodevelopmental disor-ders, such as dyslexia, autism, andhyperkinetic behavior. The reasonsfor the particular vulnerability ofthe male brain to neurodevelop-mental impairment are poorly un-derstood, but the study of genderdifferences in rates of cerebralmaturation, organization, andstructure may provide some of theanswers (see McGlone 1980; Dia-

mond 1989; Lewine et al. 1990).The role of sex hormones (ex-pressly estrogen) in early brain de-velopment should be considered inthis regard (reviewed by DeLisi etal. 1989; see Seeman and Lang1990; Hafner et al. 1991).

Female monozygotic twins havehigher concordance rates forschizophrenia than do male mono-zygotic twins (Rosenthal 1970;Kringlen 1987), and four recentstudies (Bellodi et al. 1986; Gold-stein et al. 1990a; Wolyniec et al.1992; Sham et al. 1993) haveshown that the relatives of femaleschizophrenia probands have agreater risk of developing schizo-phrenia than do relatives of maleschizophrenia probands. This find-ing might be interpreted as sug-gesting a greater role for environ-mental factors (e.g., obstetriccomplications) in male schizophre-nia, a hypothesis that is supported



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by the increasing evidence thatmale, but not female, sporadicschizophrenia patients show largercerebral ventricular volumes thantheir familial counterparts (Murrayet al. 1994; Vita et al. 1994).

Female Schizophrenia andAffective Disorder

Reviewers have tended to concludethat there is no definitive evidencefor an overall sex difference in theincidence of schizophrenia (e.g.,Hafner 1987; Lewine 1988). How-ever, when diagnostic criteria ofincreasing stringency (e.g., Re-search Diagnostic Criteria [Spitzeret al. 1978], DSM-1U-R) are ap-plied to cohorts of schizophreniapatients, more females than malesare excluded (e.g., Lewine et al.1984; Castle et al. 1993). Jones etal. (submitted for publication) haveshown that stringent diagnostic cri-teria for schizophrenia, such asthose of the DSM-IH-R, define aform of illness associated withearly onset and negative symp-toms; conversely, 41 percent offemales but only 14 percent ofmales who met Present StateExamination/CATEGO (Wing et al.1974) broad criteria for schizo-phrenia in Jones et al.'s studywere reassigned by DSM-1I1-R toaffective disorder. Bardenstein andMcGlashan (1990), reviewing gen-der differences in schizophreniaand schizoaffective and affectivedisorders, concluded that thefemale with schizophrenia is"more likely to receive differentialdiagnoses of atypical, affective, ormanic depressive illness" (p. 160)and that females are overrepre-sented among patients with a di-agnosis of schizoaffective disorder.Also, women are more susceptibleto so-called cycloid psychoses,

which are characterized by discreteepisodes of florid psychosis ofabrupt onset that tend to resolvewith good return of function be-tween episodes (Cutting et al.1978). There is some evidence thatsuch patients respond to the pro-phylactic effect of lithium (Perris1974).

Recent reviews of the relation-ship between schizophrenia and af-fective disorder (e.g., Levitt andTsuang 1988; Taylor 1992) havepointed out the complexity of theassociation and the considerableoverlap between the two in fam-ilies. Studies of familial loading inschizoaffective psychoses are diffi-cult to compare because of vari-ability in diagnostic criteria (Popeand Yurgelun-Todd 1993). How-ever, a number of studies suggestthat patients with atypical andschizoaffective psychoses showhigher than expected familial load-ing for affective disorder. For ex-ample, Tsuang et al. (1976) foundthat the siblings of their patientswith atypical schizophrenia showeda low risk for schizophrenia (1.1%)but a high risk for affective illness(7.4% vs. 6.9% in relatives of pa-tients with bipolar disorders and1.9% in typical schizophrenia com-parison groups). In reviewing thespecificity of schizophrenic symp-toms, Pope and Lipinsky (1978)found 15 studies in which famil-iality was compared in good-prognosis and poor-prognosisschizophrenia patients. Those inthe good-prognosis groups (mostlypatients with atypical, schizoaffec-tive, or schizophreniform psy-choses) typically showed two tothree times as much familial affec-tive illness as schizophrenia, whilethe poor-prognosis groups showeda twofold to threefold difference inthe opposite direction. A recentfamily interview study (Pope and

Yurgelun-Todd 1993) found highrates of affective disorder in therelatives of patients with schizo-affective illnesses, but not in rela-tives of those with schizophrenia.Sham et al. (1994), in a Scandina-vian data set, found that relativesof females with schizophrenia hada higher rate of manic depressionthan did relatives of males withschizophrenia.

Another line of evidence insupport of the notion that somefemales with schizophrenia have aform of illness with links to affec-tive disorder is the demonstrationof gender differences in season ofadmission. An excess of admis-sions for psychosis in summermonths is best established for af-fective psychosis, but studies froma number of countries have showna similar pattern in patients withschizophrenia (see Takei et al.1992). Few studies have deter-mined gender effects in seasonalityof admission. Takei et al. (1992)examined season of first admissionin 17,770 patients with schizophre-nia and 20,845 patients with affec-tive disorder in England andWales between 1976 and 1986 andfound a cyclical seasonality withan excess of summer admissionsin female, but not male, schizo-phrenia patients. A similar cyclicalpattern was seen in manic patientsof both sexes. The finding of acyclical pattern in female, but notmale, schizophrenia patients hasbeen replicated in an independentlarge data set from Scotland (Takeiand Murray 1993).

Effect of Prenatal Exposureto Influenza

Table 2 lists studies that have in-vestigated whether there is an as-sociation between prenatal ex-



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Table 2. Relationship between 1957 A2 influenza pandemicand birth of individuals who subsequently developedschizophrenia

Association andstudy

PositiveMednick et al. (1988)Kendell and Kemp

(1989)O'Callaghan et al.

(1991a)Kunugi et al. (1992)Welham et al. (1993)Fahy et al. (1993)Adams et al. (1993)2

NegativeKendell and Kemp

(1989)3

Torrey et al. (1992)Crow and Done

(1992)

Place

Helsinki, FinlandEdinburgh, Scotland

England and Wales

JapanQueensland, AustraliaEngland1

England and WalesScotlandDenmark

Edinburgh, Scotland

United StatesEngland4

Gender effectexamined

YesNo

Yes

YesYesNoNoYesYes

Yes

NoNo

Effect

Both—

Female

MaleFemale——

FemaleFemale

Female

——

'The subjects were Afro-Caribbeans.2These investigators examined three independent data sets from England and Wales,Scotland, and Denmark.3A reanalysis by Mednick et al. (1990), however, revealed a significantly increased rate ofsubsequent schizophrenic births in females.•'This study was based on the cohort from the National Child Development Study.

posure to influenza and laterschizophrenia, concentrating on the1957 A2 influenza pandemic. Ofthe 10 studies, 7 countries foundthat fetuses in utero at the time ofthe pandemic had a higher thanexpected risk of developing schizo-phrenia in adulthood. The data ofKendell and Kemp (1989), in Scot-land, were originally interpreted asnegative, but a reanalysis by Med-nick and colleagues (1990) foundan effect for females but notmales. The possible reasons for thenegative findings of Crow andDone (1992) have been discussedelsewhere (O'Callaghan et al.1991b). Although the issue remains

controversial, the weight of evi-dence appears to support a realassociation (albeit a modest one)between prenatal exposure to in-fluenza and later schizophrenia.This conclusion is supported byreports of an association betweenschizophrenic births and influenzaepidemics other than the 1957 pan-demic (Watson et al. 1984; Torreyet al. 1988; Barr et al. 1990; Shamet al. 1992; Adams et al. 1993;Morris et al. 1993; Takei et al.1994).

Are there gender differences insusceptibility to the "schizophreno-genic effect" of influenza? Regard-ing the 1957 pandemic, gender

effects were examined in sevendata sets; of these, five showedthat the effect reached significanceonly for females (see table 2). Ofthe researchers looking at influ-enza epidemics over a long timeperiod, only Takei et al. (1994) in-vestigated the effect of gender;again, the influenza effect wasmore readily demonstrable infemale than in male schizophreniapatients.

We are thus faced with theseeming paradox that females withschizophrenia show evidence ofboth greater genetic influence (i.e.,their relatives show a higher mor-bid risk of schizophrenia andaffective disorder) and greatersusceptibility to an early environ-mental effect (i.e., prenatal ex-posure to influenza). The mecha-nism whereby influenza infectionin the mother predisposes thefetus to later schizophrenia is farfrom clear (see Sham et al. 1992).Pulver et al. (1992) found thatfemale schizophrenia patients bornin winter or spring (when influ-enza viruses are most prevalent)had higher than expected familialloading for the illness; one couldinfer that the influenza effect doesnot result in "phenocopies," butrather acts in consort with agenetic diathesis. Intriguingly,Wolyniec et al. (1993) have shownthat schizophrenia patients born inwinter or spring are significantlymore likely to have a history ofmanic-like symptoms than areother schizophrenia patients andthat this effect is most marked infemales. Also, a number of studies(e.g., Myerson 1925; Slater 1936;Rosenthal 1970; Powell et al. 1973;Crow 1986) have reported a higherthan expected morbid risk ofschizophrenia in the offspring ofindividuals with affective disor-ders. Thus, one possibility is that



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the prenatal viral effect is due toa "diversion" to schizophrenia offemales who would otherwise havedeveloped an affective psychosis.Indeed, Taylor (1992), who recentlyreviewed the relationship betweenaffective disorder and schizophre-nia, suggested that "researchshould focus on ... nongeneticfactors (street drugs, perinatalproblems, viral disease) that mightalter the clinical expression of ashared genotype" (p. 29).

In a preliminary analysis, Takeiet al. (1993), examining first-admission data from England andWales for the period 1976 to 1986,found that death rates from influ-enza were associated 5 monthslater not only with an excess ofpreschizophrenic births, but with adeficit of births of females, but notmales, who later manifested affec-tive psychosis. Of course, suchfindings need independent replica-tion, but "phenotypic diversion"from affective psychosis to schizo-phrenia could go some way to-ward explaining the apparent lia-bility of females to a form ofillness resulting from maternalexposure to a virus and the pre-dominance of affective features infemales.

Conclusions

We conclude that the evidencepoints toward a differential suscep-tibility of males and females todifferent forms of schizophrenia. Inrecent years, much attention hasbeen directed toward the severeearly-onset form that predominatesin males. It is time to focus simi-lar effort on the milder, later-onsetform to which women appear par-ticularly susceptible. We are notconvinced that this is simply thesame illness ameliorated by the

antidopaminergic actions of estro-gen, but we do believe that theeffects of estrogen on cerebralstructure at the extremes of lifemerit attention. Similarly, meth-odologically rigorous researchshould be directed toward the hy-pothesis that some cases of schizo-phrenia with good outcome mayresult from an interaction betweena genetic diathesis for affectivepsychosis and environmentally in-duced brain changes.

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Acknowledgments

David J. Castle and NoriyoshiTakei gratefully acknowledge thesupport of the Medical Research

Council and Wellcome TrainingFellowships, respectively. Drs. Jimvan Os, Peter Jones, PadraigWright, Pak Sham, and ShonLewis provided useful commentson earlier drafts of the manuscript.

The Authors

David J. Castle, M.B., Ch.B., M.Sc,M.R.C.Psych., is MRC Training Fel-low and Clinical Lecturer in Psy-chiatry; Kathryn Abel, M.A.,M.R.C.P., is Research Worker; andNoriyoshi Takei, M.D., is Lecturer,Genetics Section, Institute of Psy-chiatry, London, United Kingdom;Robin M. Murray, M.D., F.R.C.P.,F.R.C.Psych., D.Sc, is Professor,Department of Psychological Medi-cine, Institute of Psychiatry andKings' College Hospital, London,United Kingdom.

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Gender Differences in Schizophrenia: Hormonal Effect … · nia, on average, show better pre-morbid functioning, later onset, and a more benign course of ill-ness. They are also more