Accepted Manuscript

Title: Sex/gender differences in the brain and cognition in

schizophrenia

Author: Adrianna Mendrek Adham Mancini-Marı̈e

PII: S0149-7634(15)30111-1
DOI: http://dx.doi.org/doi:10.1016/j.neubiorev.2015.10.013
Reference: NBR 2327

To appear in:

Received date: 30-7-2015

Revised date: 17-10-2015
Accepted date: 26-10-2015

Please cite this article as: Mendrek, A., Mancini-Marïe, A.,Sex/gender differences in the
brain and cognition in schizophrenia, Neuroscience and Biobehavioral Reviews (2015),
http://dx.doi.org/10.1016/j.neubiorev.2015.10.013

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Highlight

• evidence of sex differences in neurocognitive function in schizophrenia is

presented
• two emerging trends in the available literature have been noted:
• a) normal sex differences in the lateral frontal network and associated cognition
• b) disturbed sexual dimorphism in the corticolimbic system

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• involvement of sex steroid hormones and gender in these effects is discussed

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Sex/gender differences in the brain and cognition in schizophrenia

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Adrianna Mendrek a,b,c,*; Adham Mancini-Marïe b,c,d

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a. Department of Psychology, Bishop's University, Sherbrooke, Quebec, Canada

b. Department of Psychiatry, Université de Montréal, Montreal, Quebec, Canada

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c. Centre de recherche de l'Institut Universitaire en Santé Mentale de Montréal

d. Department of Psychiatry, Centre neuchâtelois de psychiatrie, Neuchâtel, Suisse

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*Corresponding author: 2600, rue College; Sherbrooke (QC) J1M 1Z7;

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Email: adrianna.mendrek@ubishops.ca; Phone: (819) 822 9600 (2196)

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Page 1 of 59
Abstract

The early conceptualizations of schizophrenia have noted some sex/gender

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differences in epidemiology and clinical expression of the disorder. Over the past few

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decades, the interest in differences between male and female patients has expanded to

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encompass brain morphology and neurocognitive function. Despite some variability

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and methodological shortcomings, a few patterns emerge from the available literature.

Most studies of gross neuroanatomy show more enlarged ventricles and smaller frontal

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lobes in men than in women with schizophrenia; finding reflecting normal sexual

dimorphism. In comparison, studies of brain asymmetry and specific corticolimbic

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structures, suggest a disturbance in normal sexual dimorphism. The neurocognitive

findings are somewhat consistent with this picture. Studies of cognitive functions
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mediated by the lateral frontal network tend to show sex differences in patients which
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are in the same direction as those observed in the general population, whereas studies

of processes mediated by the corticolimbic system more frequently reveal reversal of

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normal sexual dimorphisms. These trends are faint and future research would need to

delineate neurocognitive differences between men and women with various subtypes of
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schizophrenia (e.g., early versus late onset), while taking into consideration hormonal

status and gender of tested participants.

Keywords: sex differences; schizophrenia; brain morphology; neurocognitive function;

gender; sex steroid hormones

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1. Introduction

Significant sex/gender differences in schizophrenia have been noted already by

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Kraepelin (1919) who wrote: “The male sex appears in general to suffer somewhat more

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frequently and to be affected more severely by the dementia praecox” [1]. In the

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scientific literature we often use terms ‘sex’ and ‘gender’ interchangeably, but over the

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past decade several researchers suggested to be more specific and refer to ‘sex’ as a

biological variable defined principally by sex chromosomes and sex steroid hormones,

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while using the term ‘gender’ as a psychosocial construct determined mainly by family,

society and culture [2-3]. Nevertheless, it is difficult to disentangle the influence of these
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two sets of variables, as they continually interact with each other, especially in humans.

This is why we sometimes use ‘sex/gender’ throughout this paper, to indicate that in
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many discussed studies it is impossible to determine if the differences we are presented

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with were mainly due to a biological sex or a psychosocial gender, and most likely

reflected a combination of both factors. In this review we concentrate on

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neuroanatomical, neurofunctional and cognitive studies of differences between men and

women diagnosed with schizophrenia. Some of these studies have assessed sex steroid
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hormones, but gender identity and socialization was almost never taken into

consideration. Before delving into this literature, a brief introduction to schizophrenia

is in order.

2. Schizophrenia overview

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 Schizophrenia is one of the most complex and least understood psychiatric

disorders. It is typically referred to as a ‘chronic and debilitating’ condition because it

may lead to a progressive functional decline impacting cognitive, affective and social

domains [4]. However, some individuals diagnosed with the disorder function relatively

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well, maintain their employment, and have families and friends. In addition to the

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varied course of the illness, the clinical presentation of schizophrenia is also quite

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heterogeneous with symptoms ranging from hallucinations and delusions, disorganized

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speech and behavior, to flat affect, lack of motivation, and cognitive deficits [5-6]. The

symptoms are typically classified under three or four broad categories: 1) positive

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symptoms, such as delusional ideation and altered perceptual experiences; 2) negative

symptoms, including social withdrawal, avolition and poverty of speech; 3)

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disorganization, which is sometimes included under the positive category and includes

bizarre behavior and incoherent speech; 4) cognitive symptoms, such as poor

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concentration, disorientation in time and space, lack of judgment and insight, difficulties
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in abstract thinking, as well as prominent attention, executive function and memory

deficits. It is cognitive deficits that have been associated most significantly with the
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functional outcome of schizophrenia [7] and it is cognitive deficits, more specifically sex

and gender differences in the neurocognitive deficits, that are the focus of the present
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review.

In contrast to the clinical presentation and course of the illness, the onset of

schizophrenia is less varied and occurs typically in early adulthood with life-time

prevalence around 0.7-1% across different cultures [8-9]. More recent studies suggest

that the prevalence of the disorder is typically higher in developed than in developing

countries [10], and higher in migrant groups than in native-born populations [11].

Regardless of the culture, people diagnosed with schizophrenia often suffer from a wide

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Page 4 of 59
range of psychosocial difficulties and stigmatization that may be more detrimental than

the psychiatric symptoms of the disease [12-14]. Approximately 10-15% of people

diagnosed with schizophrenia commit suicide [15-16] and almost half of the patients

attempt suicide during their lifetime [17-19]. Overall, mortality in schizophrenia

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population for all causes, has been shown to be two to threefold higher than in the

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general population [20].

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The in-depth discussion of etiology of schizophrenia is beyond the scope of the

present article, but a few possible factors involved in the development of the disorder

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should be mentioned, as they may interact with sex and gender. Thus, over the past few

decades, researchers have argued for the importance of heritability, obstetric

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complications, perinatal/prenatal viral infections, severe environmental stress,

environmental toxins and hormonal perturbations [21-22]. One of the most widely
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accepted theories is that schizophrenia stems from some neurodevelopmental anomaly

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(genetic, environmental and/or hormonal), occurring most likely around the first or

second trimester of gestation. This anomaly produces faulty wiring of the brain, which
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may become behaviourally explicit during adolescence, especially if the adolescent is

exposed to high levels of stress or drug abuse [23-30]. However, the nature of the initial
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anomaly or how it leads to atypical neural wiring, and ultimately to schizophrenic

symptoms, remains unknown. There may be a wide range of early neurodevelopmental

disruptors, including specific genes or viruses, and there may be a wide range of

subsequent factors present during childhood or adolescents, including experience of

trauma and hormonal perturbations, that could individually or in combination result in

expression of schizophrenia. Thus, the prevalent view is that schizophrenia is a

polygenic/multifactorial disease [10, 31-32]. Moreover, we cannot exclude the

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Page 5 of 59
possibility of dealing with several separate disorders or at least of separate etiologies

leading to a similar clinical presentation. This is important to remember while

discussing sex/gender differences in schizophrenia, as the disorder might have slightly

different combination of etiological factors in men and women.

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3. Sex differences in the development and clinical expression of schizophrenia

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3.1. Birth complications & premorbid function

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Obstetric complications have been linked to an overall increased risk to develop

schizophrenia, an earlier age of illness onset, a poorer course of the illness and a
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ventricular enlargement [33] [34]. Several studies have examined sex differences in

these effects and found that the risk of developing schizophrenia following obstetric
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complications was higher in males than in females [35-40], and that the occurrence and
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severity of obstetric complications was more frequently associated with an early age at

onset of schizophrenia in men [35, 41]. It should be noted that obstetric complications
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might be secondary to yet earlier adverse neurodevelopmental events. One such event

is prenatal exposure to influenza. Indeed, some early studies have found an association
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between prenatal exposure to influenza in the second trimester and the later

development of schizophrenia particularly in females [42]. Altogether these findings

support a neurodevelopmental nature of schizophrenia and point to a differential

process in men and women. Further support comes from the studies of premorbid

function.

Several retrospective studies of patients, and follow-up data of women with

schizophrenia and their children, show greater premorbid deficits and more

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pronounced decline in men than in women on several aspects of the illness [43-49].

Thus, before developing schizophrenia, men tend to be more socially isolated and

withdrawn, have lower levels of education and work experience, are less able to

maintain friendships and sexual relationships, and are less likely to be married at the

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time of first hospitalization, compared to pre-schizophrenia women [45-46, 50-54]. A

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few studies did not find any sex differences in premorbid function, especially in the early

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onset schizophrenia [55-56]. Schmael and associates (2007) concluded that worse

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premorbid functioning depended on age of onset and the presence of negative

symptoms, regardless of patients’ sex [55].

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Some authors have suggested that sex differences in the premorbid function are
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due to the neuroprotective effects of estrogen in women [34, 57-58], which could also

explain other sex differences, such as milder negative symptoms, better response to
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antipsychotics, and older age of onset, in women relative to men [59-61]. Overall, it
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appears that better premorbid functioning in women, particularly in the social domain,

is partly due to their later age at illness onset, allowing to complete more years of
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education, form personal relationships, marry and find employment before the illness

takes over [47].

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3.2. Epidemiology

The incidence of schizophrenia is generally higher in men than in women, with

ratio estimates ranging from approximately 1.2 to 1.5 [62-63]. Despite relatively robust

sex differences in the incidence of schizophrenia, the lifetime prevalence rates do not

differ between the sexes in most studies [20, 62, 64-65]. However, when we consider

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Page 7 of 59
only the first half of life, up to about 40 years of age, the prevalence is higher in men,

while in the second half of life, the prevalence is higher in women. This is related to one

of the most consistent findings regarding sex difference in schizophrenia, namely 3-5

years earlier age at onset in men than in women, which has been shown to exist

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regardless of culture, definition of onset, and definition of illness [47, 52, 63, 66-74].

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Most studies report a peak of onset in men between the ages of 15-25 followed by a

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stable decline, while women seem to have a broader peak between the ages of 20-35

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with a second smaller peak between 45-49 years of age [47, 52, 64, 70-71, 75-76].

Reduced levels of estrogen after menopause have been proposed as an explanation of

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the increased prevalence in women over 40 years of age [76-77]. However, we cannot

exclude psychosocial factors, related to loneliness, isolation, lack of social support that
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may appear more frequently in menopausal and post-menopausal women and could

contribute to psychosis development [78-79].

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The sex difference in the age at onset disappears in the presence of family history

of schizophrenia [70, 80-81]. Moreover, the second peak of increased risk in women
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around menopause has been questioned by a recent recalculation of schizophrenia

incidence rates from 43 studies (total of 133 693 incident cases reported between 1950
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and 2009). According to this recalculation, men had one incidence peak between the

ages of 20-29, while women had two peaks, first between 20-29 and second between 30-

39 year of age, not as previously reported 40-49. In addition, men showed higher risk up

till the age of 39, while women showed higher risks between the ages of 50-70 [63].

Despite these new findings, sex differences in the distribution of schizophrenia risk

across the age span remain, suggesting differential susceptibility to schizophrenia for

men and women at different stages of life.

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3.3. Symptomatology

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In addition to the earlier age at onset and greater premorbid dysfunction, men

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with schizophrenia typically present with more prominent negative symptoms relative

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to women [82-88]. The negative symptoms include social withdrawal, blunted affect,

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lack of motivation and poverty of speech, and start appearing two to six years before the

diagnosis [75]. Women, on the other hand, have been found to exhibit more affective

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symptoms, including depression, impulsivity, inappropriate affect, sexually

inappropriate behavior, sexual delusions and other atypical positive symptoms [84, 89-
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95] although this finding has been less consistent [96]. Most of these symptoms start

developing one to two years before the first hospitalization [75].

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It should be noted, that similarly to the age of onset, sex differences in negative
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symptoms have been reported to disappear in familial schizophrenia and in cases where

schizophrenia was associated with advanced paternal age [97]. Moreover, there are
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several studies, which reported similar frequency and severity of positive symptoms in

men and women with schizophrenia [98-101]. In some recent studies, symptoms have
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been differentially linked to cognitive function in men and women. For example,

negative symptoms were shown to affect verbal recall and verbal fluency in male

patients, whereas attention disorders affected these abilities in female patients [102].

Developing further the association between clinical symptoms and cognitive deficits,

Brebion and associates (2013) found that depression symptoms affected verbal recall in

women, whereas anxiety affected it in men [103]. This leads us to the main focus of this

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Page 9 of 59
review – the brain and cognitive sex differences in schizophrenia, which are discussed in

a subsequent section.

4. Sex/gender differences in brain structure of schizophrenia patients

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4.1. Gross neuroanatomy

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One of the most robust neuroanatomical findings in schizophrenia is the

enlargement of ventricles and related decreases in the total brain volume and in cortical

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and subcortical tissue, which appear to be particularly pronounced in the prefrontal

cortex (PFC), superior temporal cortex and the hippocampal formation [104-108]. This
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increased ventricular-brain ratio (VBR) has been observed in chronic as well as first-

episode patients, in men and in women, but both illness duration and sex/gender have
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been associated with severity of VBR.

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The early studies attempting to elucidate sex differences in brain anatomy of

schizophrenia patients produced mixed results, but the general consensus has been that
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men present with more severe morphological abnormalities than women, including

reduced frontal and temporal volumes (especially medial temporal lobe and superior
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temporal gyrus), as well as larger VBR [47, 62, 109-116]. For example, Andreasen and

colleagues [84, 110] and subsequently Nopoluos and colleagues [117] observed a sex-

by-diagnosis interaction for the ventricular volumes. Men diagnosed with schizophrenia

had significantly larger ventricles relative to the same-sex controls, while in women

patients the ventricular enlargement was significantly less pronounced or non-existent.

In a study of temporal lobe structures, Bryant and colleagues (1999) found that when

men and women patients were grouped together, they showed overall smaller volumes

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in the superior temporal gyrus and the amygdala/hippocampal complex relative to

controls. However, when two sexes were analyzed separately, the left temporal lobe

volume was significantly smaller in men patients only [118]. It has to be mentioned that

some studies of that period did not find any significant sex differences [119-121] or

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reported greater deficits in women relative to men [122].

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The earlier neuroanatomical studies used computed tomography (CT) or lower

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resolution magnetic resonance imaging (MRI), while later reports relied more

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frequently on higher fields and better resolution MRI, as well as more sophisticated

analyses (see for example a series of studies by Narr and associates; [123-128]). Thus,

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Narr and colleagues (2000) performed 3D MRI of the corpus callosum in 15 men and 10

women with schizophrenia and in matched healthy controls. The results revealed
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significant increases in maximum widths in anterior and posterior regions in men with

schizophrenia relative to the same-sex controls [126]. Displacement and curvature

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increases were highly correlated with structural differences in surrounding

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neuroanatomical regions, including increased volume of the lateral ventricles. The

researchers suggested that women with schizophrenia might be less vulnerable to

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ventricular enlargement and to alterations in surrounding neuroanatomical regions

compared to men patients [126]. A subsequent study by the same group revealed a sex-
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by-diagnosis interaction with schizophrenia males showing a greater loss of superior

temporal sulcal slope asymmetry in the right hemisphere relative to schizophrenia

females [129]. In addition, the researchers found greater variability in the longitudinal

fissure, reflecting both larger sulci and larger cerebrospinal fluid (CSF) volume in males

relative to female patients. In yet another study, Narr and associates (2003) examined

the effects of sex and age on the cortical grey matter and CSF volume in chronic

schizophrenia patients relative to healthy controls, using automated measuring methods

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in MRI images. The analysis showed specific increases in the sulcal and subarachnoid

CSF that appeared prematurely in men diagnosed with schizophrenia, while women

patients showed normal aging effects [125].

In a CSF study by a different group, Molina and colleagues found that only men

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with schizophrenia showed significantly more CSF in the left prefrontal area, due to

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probable grey matter loss. Moreover, CFS values in the prefrontal and temporal regions

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were positively correlated with illness duration in men, but not in women, supporting

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hypothesis of accelerated prefrontal cortical loss in males, but not in females with

schizophrenia [130]. In a study by Yotsutsuji and colleagues (2003), the lateral

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ventricles were divided in four compartments: anterior horn, body, posterior horn and

temporal horn using 3D MRI and then the total hemispheric volumes, the four
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subdivisions of the lateral ventricles, as well as the third ventricle were measured. As

predicted, bilateral hemisphere volumes were significantly lower in patients than in the
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controls. Moreover, male patients had significantly increase volumes in the left
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temporal horn, bilateral anterior horns, the right body, as well as the third ventricle.

Women patients showed similar, but less pronounced ventricular enlargements [131].
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In terms of other cortical anomalies in schizophrenia, Frederikse and colleagues

(2000) investigated grey matter volume in the inferior parietal lobule (IPL), which has
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been reported to be larger in men than in women in the general population, and to have

a left-greater-than-right asymmetry in men only. The analysis revealed that men with

schizophrenia had a reversal of the normal asymmetry (i.e., they had right-greater-than-

left IPL), as well as significantly decreased left IPL volume compared to control men. In

contrast, no significant differences in asymmetry or volume were observed in women

patient relative to the same-sex controls [132]. In a similar study, Collinson and

colleagues [133] explored hemispheric brain volume, brain asymmetry and IQ in the

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early-onset schizophrenia patients. The results showed that the total brain volume was

significantly smaller in patients relative to controls, especially in the left hemisphere of

men. The reductions in volume correlated with lower IQ measures in patients. In

addition, a significant sex-by-diagnosis interaction was observed. Women patients

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showed significantly reduced right more than left asymmetry, while men patients

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showed decreased left more than right asymmetry, relative to the same-sex controls

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[133].

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Brain asymmetry or cerebral torque, where the right frontal lobe is larger than

the left, while the left occipito-temporo-parietal part of the brain is larger than the right,

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is due to the development of neural connections associated with language: from right to

left in relation to the motor speech output and from left to right in relation to speech
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perception [134-135]. Disturbance in this neural development has been proposed as the

basis of the genetic predisposition to psychosis [136]. In other words, schizophrenia

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may be a result of an abnormal cerebral lateralization, which in turn is believed to have

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evolved in order to allow for language development in humans [134-135]. In a recent

study of torque, in adolescent-onset patients with schizophrenia, Savadjiev and

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colleagues (2014) examined white matter geometry using diffusion tensor imaging

(DTI) in 22 men and 17 women diagnosed with schizophrenia, and in 16 men and 17
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women controls. In the general population the male brains tend to be more asymmetric

than the female brains, however in schizophrenia patients the situation was reversed.

Moreover, these abnormalities were correlated with negative symptom severity in a sex-

specific manner [137]. Thus, in male patients severity of negative symptoms was

correlated with a reduction in connection asymmetry, while in female patients stronger

negative symptoms were related to increase in asymmetry.

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4.2. Gyrification

In addition to the brain volume and brain asymmetry, a few studies have

investigated sex-specific and sex-dependent gyrification abnormalities in schizophrenia.

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In one of the earliest studies of this type, Bullmore and colleagues (1995) showed a

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global reduction in the right hemisphere radius of gyrification in males but not in

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females with schizophrenia [138]. In a different study, Vogeley and associates (2000)

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examined postmortem brains of patients (N=24) and healthy controls (N=24) using

gyrification measures specifically in the prefrontal region. The researchers found a

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significant diagnosis-by-sex interaction in the right prefrontal cortex, where men

patients had higher gyrification index (GI) in comparison to healthy men, while no
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significant differences were observed between two women groups [139]. Similar results

were subsequently obtained in the living first episode patients by Narr and colleagues
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(2004) who used MRI to measure 3D gyral complexity in five cerebral regions: superior
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frontal (dorsolateral), inferior frontal (orbitofrontal), temporal, parietal and occipital.

The study included 33 men and 17 women with first episode schizophrenia and sex and
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age-matched controls. The analysis showed significant increases in cortical folding in the

right superior frontal cortex in male patients compared to controls, while no differences
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were observed in women [123]. The abnormality appeared to predate illness onset in

men only, suggesting sexually dimorphic developmental origin of schizophrenia

occurring likely during organization of cortical folding in utero.

Our group has also conducted a study investigating differences in the GI between

patients with schizophrenia and healthy controls while taking into consideration sex,

age and illness duration [140] . Schizophrenia patients (24 men and 24 women) and

healthy volunteers (24 men and 24 women) matched for age, sex and handedness were

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assessed. The main findings revealed: (1) significantly lower values of the overall GI in

schizophrenia relative to normal controls; (2) significantly lower values of the GI in the

right hemisphere in men with schizophrenia compared to the same-sex controls and no

differences between women groups; (3) hemispheric GI values decrease with age in

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healthy controls (with no sex difference) and in patients (greater in men than in

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women), with a more progressive deterioration in the right hemisphere in

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schizophrenia; (4) significant GI values decrease with the duration of illness in

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schizophrenia men but not in schizophrenia women; (5) patients exhibited lower GI

compared to the control group in the bilateral frontal and parietal and left temporal

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cortex (6) sex-by-illness duration interaction, such that men patients showed more

rapid decrease in the right parietal and occipital GI, while women showed more rapid
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decrease in the left frontal and right temporal GI. In short, consistently with other

studies [123] we did observe a diminished GI in schizophrenia men relative to control

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men, but no difference between women groups, suggesting somewhat different

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neurodevelopmental processes involved in male and female patients. This supposition

was strengthened by the covariate analyses, which revealed a significant relationship

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between a decrease in the GI and age as well as illness duration in schizophrenia men,

but not in schizophrenia women [140] .

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Despite numerous studies reporting sex-dependent and sex-specific differences

in the gross neuroanatomy, asymmetry and gyrification in schizophrenia, a recent meta-

analysis by Haijma and colleagues (2013), which included 317 studies involving

approximately 18000 subjects with over 9000 patients with schizophrenia, has found

only modest anatomical differences between men and women with schizophrenia. The

meta-analyses aimed at investigating structural brain differences in patients with

schizophrenia in relation to potential modifying factors such as duration of illness, sex

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composition, current antipsychotic dose, and intelligence quotient. In terms of sex

differences, the results showed that reduced intracranial volumes and decreases in

white matter tissue were relatively more pronounced in men than in women with

schizophrenia [141]. The authors speculated that since intracranial volume reaches

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approximately 90% of its final volume at the age of 5 years and no further changes occur

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to its final volume after the age of 14, thus the more pronounced intracranial reductions

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in men patients may be attributed to a more severe or earlier neurodevelopmental

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abnormalities. There is a possibility that finer neuroanatomical sex differences (e.g.

hippocampus and amygdala) could not be elucidated in this review. These are discussed

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next.
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4.3. Corticolimbic system
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We reach a point in our discussion when a distinction between normal and

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atypical sexual dimorphisms becomes evident. So far, the gross neuroanatomical results

of larger ventricles as well as reduced frontal and temporal volumes, in men relative to
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women with schizophrenia (discussed above), revealed differences in the direction of

normal sexual dimorphism (for a recent meta-analysis of brain sex differences in the
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general population please see Ruigrok et al., 2014 [142]). In comparison, studies of

brain asymmetry as well as studies of circumscribed brain areas (discussed below),

elucidated sex differences, which were sometimes in the direction opposite to the

normal sexual dimorphism. Thus, the normal pattern of morphological sexual

dimorphism has been shown to be disrupted in schizophrenia in several corticolimbic

regions including: amygdala, hippocampus, hypothalamus, as well as orbitofrontal,

anterior cingulate and insular cortex.

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 Gur and colleagues performed a series of thorough morphological studies with

large sample sizes ranging from 100 to over 200 participants. In one study they

investigated different parts of the prefrontal cortex and found that gray matter volume

in the dorsolateral area was reduced in both men and women, the dorsomedial region

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was reduced only in men, while orbital region was reduced only in women [112]. In

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another study [113] examining temporolimbic regions, they found comparable

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hippocampal and temporal pole reductions in men and women with schizophrenia, but

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in the amygdala decreased volume was evident in men and increased volume was

evident in women. These surprising sex differences were explored further in a study of

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31 neuroleptic-naïve schizophrenic patients (15 women) and 80 healthy volunteers (46

women), which focused specifically on the orbitofrontal cortex to amygdala ratio (OAR)
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[143]. The OAR is typically higher in healthy women than in healthy men. However, in

schizophrenia the situation was reversed. Thus, men patients had increased OAR
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relative to healthy men, mainly due to reduced amygdala volumes, whereas women
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patients had decreased OAR relative to the same-sex controls, mostly due to reduced

orbitofrontal volumes. Reversed sexual dimorphism was demonstrated by the same

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group in other studies [144-145]

The amygdala has been also investigated by Niu and colleagues (2004) in 20 men
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and 20 women diagnosed with schizophrenia and in 40 age- and sex-matched controls

[146]. Consistently with the findings by Gur and colleagues [112, 143] only male

patients had significantly reduced volumes in the bilateral amygdala relative to the

same-sex controls. Furthermore, a significant left-smaller-than-right volumetric

asymmetry of the amygdala was detected only in men and not in women with

schizophrenia [146]. In a more recent study, Takayanagi and associates [147] applied

both volumetric and cortical thickness measures in 3D MRI of 29 men and 23 women

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with first episode schizophrenia and in 22 men and 18 women controls. Consistently

with the majority of structural findings, patients showed gray matter volume reductions

and cortical thinning in prefrontal and temporal cortices compared with controls. In

addition, sex differences were found in the bilateral amygdala, with more reductions in

t
men than women with schizophrenia [147].

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The amygdala is heavily interconnected with multiple brain regions, especially

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hippocampus with which it mediates emotional salience and memory [148]. The

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hippocampus has been implicated in the neuropathology of schizophrenia for a few

decades [149], but only recently Irle and colleagues [150] investigated hippocampal

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volume in relation to illness duration separately in 23 men and 23 women with

schizophrenia. The researchers found that only men with schizophrenia had
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hippocampal volume reductions relative to the same-sex controls at the illness onset,

but with longer illness duration women had similarly reduced hippocampal size as male
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patients. Indeed only women patients were characterized by an inverse relationship

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between the hippocampal volume and illness duration [150].

Another region frequently linked with schizophrenia – anterior cingulate cortex

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(ACC) - is anatomically associated with the corpus callosum and functionally implicated

in a wide range of autonomic, cognitive and affective functions including decision

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making, error detection, reward anticipation, emotion and empathy. In an elegant study

where multiple cortical and subcortical brain regions were segmented and analyzed,

Goldstein and colleagues (2002) found volume reductions in ACC in women but not in

men with schizophrenia, relative to the same-sex controls [151]. In the general

population it is women who typically present with greater grey matter volume of ACC

than men [152], while in case of the patients the situation was reversed. This finding

was supported by subsequent studies in schizophrenia [153] and in schizoaffective

18
Page 18 of 59
disorder [154]. Takahashi and associates (2002) found that right anterior cingulate was

significantly reduced only in women with schizophrenia. Moreover, women patients

lacked the normal structural asymmetry - right larger than left ACC. Contrary to

prediction that men with schizophrenia would show more laterality disruption, they did

t
not differ from the same-sex control group on any measures [153]. In the following

ip
study, the same group of researchers [155] tried identifying which part of ACC show

cr
most pronounced abnormalities in schizophrenia relative to healthy controls. They

us
found a significant sex difference in the perigenual cingulate gyrus in control subjects

where women had larger grey matter volumes than men. This difference was not

an
significant in schizophrenia due to reduction in bilateral perigenual cingulate gray

matter in female patients compared with female controls and no differences between
M
the men groups.

Another important region of the limbic system – hypothalamus – involved in the

d

regulation of endocrine system and motivated behavior, has been examined by

te

Goldstein and associates (2007) who was the first to demonstrate that, contrary to
p

expectations, hypothalamic volumes in schizophrenia patients were significantly larger

ce

than those in normal controls. These abnormalities were also present in nonpsychotic

relatives of schizophrenia patients; they were positively correlated with anxiety and
Ac

were more pronounced in women [156]. Finally, sex-specific differences have been

reported by Duggal and colleagues (2005) in the insular volume in never treated

patients with first episode schizophrenia. Similarly to ACC, insula is implicated in

various functions ranging from regulation of autonomic system, bodily self-awareness

and interoceptive awareness of body states, to pain perception, emotion and empathy.

19
Page 19 of 59
The researchers have found that women with schizophrenia had significantly reduced

right insular volume relative to healthy women, while there was no effect in men [157].

Sex-dependent and sex-specific structural differences and their relation to

cognitive deficits have been addressed only in a few studies [112-113]. For example,

t
ip
Abbs and colleagues (2011) examined PFC, IPF, ACC, hippocampal region in relation to

cr
verbal memory function, which tends to be preserved in women relative to men with

schizophrenia. Male patients showed volumetric reductions in all examined structures

us
except for ACC, and their reductions in the hippocampus and PFC were correlated with

memory performance, which was more impaired than in women patients. In

an
comparison, female patients had a decreased ACC volume relative to the same-sex

controls, and their ACC reduction was correlated with memory performance [158].
M
To conclude, majority of gross neuroanatomical studies of total brain volume,
d

ventricular volume and VBR, point to the overall greater deficits in men that in women
te

with schizophrenia. However, the studies of brain asymmetry and of more

circumscribed brain regions, especially those comprising the limbic system, reveal a
p
ce

more nuanced picture; some results show typical sex differences in schizophrenia

patients, while other data show diminished or reversed normal sexual dimorphism. The
Ac

behavioral and functional neuroimaging studies, reviewed below, parallel this

complexity.

5. Sex/gender differences in cognitive function of schizophrenia patients

Given the reports of more severe gross neuroanatomical abnormalities and more

negative symptoms in men relative to women with schizophrenia, one would also expect

20
Page 20 of 59
to observe more neurocognitive deficits in male patients, but the available evidence is

less straightforward. Thus, some studies have reported superior cognitive function in

women relative to men patients, others found the opposite effect or no sex /gender

difference, while some observed a reversal of normal sexual dimorphism. These are

t
discussed below.

ip
cr
5.1. Greater deficit in men than in women with schizophrenia

us
Some of the earlier studies by Goldstein, Seidman and associates [159-160] in

an
chronic schizophrenia outpatients, documented overall worse performance in men

relative to women on a variety of cognitive tasks. In one study, both sexes exhibited
M
deficits on the executive function (measure by the Wisconsin Card Sorting Test;

indicative of dorsolateral prefrontal cortex deficit) and on the olfactory identification

d

(assessed by the University of Pennsylvania Smell Identification Test; sensitive to the

te

medial and orbitofrontal damage) relative to controls, but the impairment was more

pronounced in men relative to women with schizophrenia [160]. In a subsequent study,

p
ce

which used an extensive neuropsychological battery, men with schizophrenia were

impaired across all cognitive domains in comparison with the same-sex controls, and on
Ac

tests of attention, verbal memory, and executive functions relative to women patients.

Women with schizophrenia were also impaired in comparison to healthy women, but

only on the tests of attention, executive functions and visual memory, suggesting that

they may be less vulnerable to deficits in verbal processing than schizophrenia men

[159]. Sota and Heinrichs (2003) evaluated verbal memory in 70 males and 36 females

diagnosed with schizophrenia, using the California Verbal Learning Test (CVLT) and

found that men performed worse than women on both cumulative learning and the

21
Page 21 of 59
absolute number of words recalled. There was no control group included in the study,

but the pattern of results seemed to resemble sex differences in the general population

with a suggestion of a greater relative deficit in men patients. It is worth mentioning that

antipsychotic dose (chlorpromazine equivalent) was negatively related to learning and

t
recall in both sexes [161].

ip
More recently, Vaskinn and associates (2011) tested 154 schizophrenia patients

cr
(60 women), 106 bipolar I disorder patients (55 women), and 340 healthy controls (158

us
women) with an extensive neuropsychological test battery including CVLT. Predictably,

both clinical groups performed worse than controls on most cognitive tests. In addition,

an
men with schizophrenia performed disproportionally worse relative to their female

counterparts on the CVLT, Color-Word Interference, and Interference/Switching tests

M
[162]. In a similar study, Han and colleagues (2012) [163] evaluated cognitive function

in 200 patients with schizophrenia (78 women) and 271 healthy controls (130 women).
d

The patients were overall impaired on the immediate and delayed memory, language, as
te

well as a total score on the Repeatable Battery for the Assessment of Neuropsychological

Status (RBANS), which in turn showed moderate inverse correlation with symptom
p
ce

severity, illness duration and antipsychotic dose. Moreover, men with schizophrenia

had significantly more serious cognitive deficits than women patients in immediate and
Ac

delayed memory, but not in language, attention or visuo-spatial processing. In another

study from the same group, with an impressive sample size of 262 unmedicated first-

episode and 960 chronic schizophrenia inpatients, as well as 804 matched healthy

controls, both first-episode and chronic schizophrenia patients performed worse than

controls on most cognitive tasks. However, while relative to the chronically ill women,

men with chronic schizophrenia were more impaired on attention, delayed memory and

immediate memory, there were no sex/gender differences in the first-episode patients

22
Page 22 of 59
[163]. These results paralleled the clinical status of tested patients; chronically ill

women had more severe positive and general psychopathological symptoms, whereas

chronically ill men had more severe negative symptoms. In contrast, first-episode

schizophrenia patients showed no sex/gender differences in symptomatology. The

t
issue of first-episode vs. chronic schizophrenia reappears in some other studies

ip
discussed in subsequent sections. Finally, in a study of mentalizing abilities, which are

cr
typically impaired in schizophrenia, Abu-Akel and Bo (2013) found that clinically stable

us
men were more impaired than women patients. Women were superior in their ability to

attribute and understand affective mental states of others and the observed sex/gender

an
differences were unrelated to intelligence or symptomatology [164]. Unfortunately the

researchers did not include the control group, but their results highlighted the
M
possibility that sex differences in schizophrenia are not limited to classic cognitive

domains, such as memory, language or visuo-spatial processing, but may also

d

encompass social cognition, including theory of mind, empathy and emotion recognition.
te

5.2. Greater deficit in women than in men with schizophrenia

p
ce

Only a few studies have shown better cognitive performance in men relative to
Ac

women with schizophrenia [165-167]. For example, Perlick and associates (1992)

evaluated schizophrenia inpatients and outpatients, but no controls, and found that

women in both clinical groups had greater deficits than men on attention and

conceptualization tasks. In addition, a sex-by-group interaction was present for

construction scores with women performing worse than men among inpatients, and

better among outpatients [165]. In this study women had atypically early age of

schizophrenia onset, which could partially account for the unexpected results. In a

23
Page 23 of 59
different study, Roesch-Ely and colleagues (2008) assessed working memory and

executive control in 50 partially remitted inpatient (25 women) and in 40 comparison

participants (20 women). There were no apparent sex differences in the healthy

controls, while among patients there were no sex differences in the working memory

t
function, but women were more impaired than men on the executive control dual-task

ip
[168]. As in the aforementioned report, in this study the patient sample was also

cr
somewhat atypical, as men presented with more positive symptoms than women.

us
Lewine and colleagues (1996) administered an extensive neuropsychological battery to

195 patients (63 women) with schizophrenia or schizoaffective disorder, and to 99 (60

an
women) healthy controls. Contrary to the expectation, women patients had relatively

greater deficits than men patients on visual processing, as well as verbal and spatial
M
memory [166]. In addition, women patients had worse right than left hemisphere

performance, whereas male patients had identical scores for right and left hemisphere
d

impairment. These cognitive findings parallel some neuroanatomical sex differences in

te

brain asymmetry in schizophrenia, discussed earlier [137].

p
ce

Sex differences in schizophrenia onset, symptomatology and antipsychotic use,

are often regarded as confounding variables in neurocognitive studies. There is still no

Ac

consensus on the best strategy to deal with these issues. Should we try matching as

closely as possible men and women on all clinical variables, or should we compare a

typical male with a typical female presentation of schizophrenia? In an elegant study

that tackled some of these questions, Lewine et al (1997) reported an enlightening

interaction between onset and sex in schizophrenia patients. Specifically, the

researchers found more impaired cognitive performance and less lateralized function in

early-onset men and late-onset women compared with late-onset men and early-onset

24
Page 24 of 59
women. In other words, early-onset men resembled late-onset women and were more

severely affected, while late-onset men were more like early-onset women and were less

severely affected [167]. This topic should be explored in future research.

t
ip
5.3. Lack of sex/gender differences

cr
us
A deliberate matching of men and women with schizophrenia on clinical

variables, or accounting for existing differences in the analysis, can sometimes change

an
results and conclusions. For example, Hoff and colleagues (1998) found that chronic

male patients performed worse than female patients on visual memory measures, but
M
these differences were eliminated after controlling for symptom severity [169]. A few

other studies did not find any differences between men and women in cognitive
d

performance, but they did not include healthy comparison participants [89, 170-171].
te

Andia and colleagues (1995) tested 85 outpatients (32 women) with schizophrenia and

did not find any significant differences between men and women on neurocognitive
p
ce

function or symptom severity. Nevertheless, women in the sample were on lower doses

of antipsychotic medication and more frequently met the criteria for paranoid and
Ac

disorganized subtype of schizophrenia [89]. Goldberg and associates (1995) compared

neuropsychological test performances of men and women who were chronically ill or

just admitted to the hospital and did not find any significant sex/gender differences.

However, the researchers cautioned that the results of their study were relevant only for

patients with schizophrenia onset before the age of 30, as the sample did not include

later ages of onset, which are more typical in women [170]. More recently, Kao and

colleagues (2012) tested 73 (34 women) middle-aged outpatients on a battery of

25
Page 25 of 59
neuropsychological tests and did not find any differences between men and women.

The absence of control participants prevents us from concluding if the lack of cognitive

sex differences represented a typical or a distorted sexual dimorphism.

In a study, which examined neuropsychological performance across psychotic

t
disorders, including schizophrenia/schizoaffective, bipolar/manic and psychotic

ip
depressive disorders, Zanelli and collegues (2013) observed a disorder-specific

cr
sex/gender differences in neurocognitive performance. Thus, men and women with

us
schizophrenia/schizoaffective disorder showed similar pervasive impairments, while in

psychotic depressive disorder, and to some extent in bipolar/manic disorder, women

an
performed worse than men. The deficits in all disorders were assessed relative to the

group of healthy controls [172]

M
5.4. Mixed results depending on cognitive domain
d
te

It is important to remind the reader that in the general population some subtle

sex/gender differences in cognitive function have been reported. Thus, men tend to
p
ce

outperform women on some spatial skills (e.g., mental rotation) while women, on

average, perform better on some verbal tasks (e.g., verbal episodic memory) [[172].
Ac

Similar differences have been found in schizophrenia implying that normal sex

differences are preserved [173-174]. However, some studies have found that sex

differences in cognitive function might be diminished or even reversed [175-177].

5.4.1. Preserved sexual dimorphisms

In one early study, which claimed explicitly lack of cognitive sex differences in

schizophrenia, Albus and colleagues (1997) have indeed found differences between

26
Page 26 of 59
male and female patients, but these differences were in the same direction as those

observed in the control participants. Thus, women performed better on verbal memory

and learning, while men performed better on spatial organization tasks. There were no

differences between schizophrenia patients and controls, except for similar deficits in

t
both sexes on the visual motor processing, attention and verbal memory and learning

ip
[178]. Halari and colleagues (2006) employed a sexually dimorphic cognitive battery,

cr
which included tests of spatial and verbal abilities, to evaluate performance of 43 (21

us
women) schizophrenia patients relative to 42 (21 women) healthy controls. The

patients performed overall worse than controls, but exhibited the same pattern of

an
sex/gender differences, with men outperforming women on mental rotation and line

orientation, while women outperforming men on phonological and semantic fluency

M
[174]. In a similar vein, Bozikas and associates (2010) administered a comprehensive

cognitive battery, which included some sexually dimorphic tests, to 96 (40 women)
d

schizophrenia patients and 61 (30 women) comparison subjects and did not find any
te

significant group by sex interaction. Male and female patients were impaired on most

cognitive domains, but the female advantage on the verbal learning and memory tasks
p
ce

was present in both patients and controls [173].

Ayesa-Arriola and associates (2014) tested patients with first episode psychosis
Ac

and control subjects, and found that women scored higher than men on verbal memory,

whereas men scored higher than women on visual memory and planning tasks. There

were no group-by-sex interactions for any of the neuropsychological tests, but patients

performed worse than controls on most tasks. Despite the overall lack of sex-specific

differences in cognitive performance in the first episode psychosis, there was evidence

that women with a late onset may represent a subgroup with a specific impairment in

visuo-spatial processing and problem solving [173]. This finding echoes some of the

27
Page 27 of 59
earlier studies examining typical versus late onset schizophrenia [167], and deserves

further examination. In another recent study, Ittig and colleagues (2015) also evaluated

cognitive performance of first episode patient, as well as individuals at-risk for

developing psychosis and healthy controls. The results showed that women performed

t
better on verbal learning and memory, while men had a shorter reaction time during the

ip
working memory task, regardless of a diagnostic group [173].

cr
The studies presented in this section suggest that cognitive sexual dimorphism remains

us
undisturbed in schizophrenia patients, but a comparable number of reports, discussed

in the next section, reveal a different story.

an
M
5.4.2. Diminished or reversed sexual dimorphism
d

A few studies of cognitive function in schizophrenia, which have argued for the
te

absence of any sex differences or for a typical sexual dimorphism, contain hints of a

perturbation of normal sexual dimorphism. For example, Torniainen and collegues

p
ce

(2011) tested 218 participants with schizophrenia, 438 of their healthy first-degree

relatives, and 123 controls, and concluded that sex differences in cognition were similar
Ac

across the groups. Nevertheless, there was a significant group-by-sex interaction on

some measures. Specifically, while women outperformed men in the relatives group on

immediate verbal recall and the use of semantic clustering as a learning strategy, there

was no sex difference in the schizophrenia group [179]. Similarly, Shipman and

associates (2009) did not find any sex differences on memory for object location in

schizophrenia patients, but observed significant sex differences in the group of controls

[180].

28
Page 28 of 59
 In one of our studies, we found a reversal of normal sexual dimorphism on a

mental rotation task [181]. The task was used specifically for its already validated

sensitivity to sex differences in healthy controls [182-189]. We replicated the finding of

superior performance of men relative to women on this task, but in the patients

t
population the pattern was reversed. However, a closer look at the group-by-sex

ip
interaction revealed that it was mainly due to a significant deficit in male patients and a

cr
normal performance in female patients, relative to the same sex-controls. Another

us
study, which investigated visuospatial abilities in 43 women and 66 men with

schizophrenia, found that women demonstrated higher contour integration scores, but

an
lower performance on the context sensitivity index of presented shapes compared to

men with schizophrenia [190].

M
In addition to “cool” cognitive processes, such as attention and memory, patients

with schizophrenia tend to exhibit deficits in “hot” functions, including social cognition,
d

emotion processing and smell identification. In a series of studies examining olfaction

te

and cognition in schizophrenia, Malaspina and colleagues [176-177] uncovered some

interesting sex-specific effects. In the first study, the researchers found that while in
p
ce

healthy males increased odor detection predicted better smell identification, in male

patients there was an inverse relationship between these two variables. In women, on
Ac

the other hand, odor sensitivity and smell identification were unrelated regardless of the

diagnostic group. Importantly, olfactory processing was strongly linked to negative

symptoms. However, in men emotional expression deficits were related to impairment

of smell identification, whereas in women emotional deficits were linked to odor

detection hypersensitivity [176]. In a subsequent study, sex modified relationships of

odor identification to cognitive performance, including significantly stronger

correlations of smell identification with memory and attention, in females than in male

29
Page 29 of 59
with schizophrenia. On the other hand, correlations of odor sensitivity with various

cognitive measures were either weaker in women or contradicted the correlations

observed in men [176]. In a different study, Strauss and associates (2015) evaluated a

relationship between endogenous oxytocin levels and the perception of emotion in

t
dynamic body expressions in schizophrenia. The results revealed that patients were

ip
less accurate at identifying emotions than controls and that they had significantly higher

cr
plasma oxytocin, which was positively correlated with task performance in both patients

us
and controls. Importantly for our discussion there was a significant group-by-sex

interaction, such that control women were more accurate than control men, whereas

an
schizophrenia women were less accurate than schizophrenia men [191]. We have

obtained comparable brain activation results in the fMRI studies of emotional memory
M
discussed in the subsequent section.

A review by Mesholam-Gately and collegues (2009) concluded that most studies

d

addressing sex differences in cognitive function of schizophrenia were not adequately

te

designed [192]. Others agree that the existing literature remains largely inconclusive
p

[47, 193]. In addition to shortcomings in design (e.g. lack of appropriate control group;
ce

unexplored or unexplained between-group differences in symptomatology, medication

status, illness onset and illness duration) one of the difficulties encountered while trying
Ac

to interpret the available literature has been an enormous variability in the employed

tests. It would be much easier to elucidate meaningful results if, in addition to tasks

designed to assess specialized functions, a standard neuropsychological battery were

employed by everyone. Despite the fact that the ensemble of studies on cognitive sex

differences in schizophrenia is difficult to interpret, we would like to propose two faint

patterns that seem to emerge. First, it appears that in chronic schizophrenia, men

30
Page 30 of 59
present with more cognitive deficits than women [159-160], but this difference may be

less pronounced or nonexistent during early years of the illness [163, 194]. In addition

to chronicity, the early versus late onset needs to be carefully investigated, as a few

studies have already suggested that cognitive profiles may depend on illness onset,

t
particularly in women [167, 194]. Second, the studies of “cool” cognitive processes,

ip
mediated by the lateral frontal cortex and fronto-parietal network, tend to show typical

cr
sexual dimorphism in schizophrenia [174, 195], while the studies of “hot” cognitive

us
processes, mediated by the ventromedial prefrontal cortex and the limbic system, more

frequently show reversal of normal sexual dimorphisms [176, 191]. The latter results

an
are consistent with neuroanatomical studies showing reversal of normal sexual

dimorphism in schizophrenia in the anterior cingulate, the orbitofrontal cortex and the
M
amygdala [143, 151].
d
te

6. Sex/gender differences in brain function of schizophrenia patients

p
ce

Numerous studies of sex differences in brain structure and cognitive function in

schizophrenia have been published, while the functional neuroimaging literature

Ac

remains very modest in comparison. We have carried out several studies of sex and

gender differences in the neural function associated with cognitive [175, 196] and

emotion processing [197-198] and found some alterations of a normal sexual

dimorphism. Thus, in one of the earliest studies we implemented functional MRI (fMRI)

during exposure to aversive stimuli and found that men with schizophrenia exhibited

more widespread and more intense activations than women patients, in similar brain

regions where women would normally exhibit greater activations relative to men in the

31
Page 31 of 59
general population (e.g. cingulate gyrus, temporal cortex, cerebellum [197]. Subsequent

investigations revealed that the symptom profiles in men and women correlated

differently with brain activations during processing of emotional information [197]. In a

different study, we used an electroencephalography event-related potentials

t
(EEG/ERPs) to evaluate sex differences in the neural correlates of episodic memory in

ip
schizophrenia. We found that the direction of sex differences depended on the cognitive

cr
processes being examined. For instance, early frontal processes (related to interference

us
inhibition) revealed an interaction between sex and diagnostic group suggesting a

reversal of normal sexual dimorphism in our schizophrenia sample, while analysis of

an
late posterior processes (related to mnemonic binding process) resulted in sex

differences in the same direction in both schizophrenia patients and healthy controls
M
[196]. The fMRI study of visuo-spatial processing also brought some unexpected results.

Thirty-tree (17 women) clinically stable schizophrenia patients and 35 (17 women)
d

controls performed a classic mental rotation task while in the scanner [175]. Behavioral
te

results confirmed already discussed group-by-sex interaction [199] and the fMRI data

paralleled these findings. Thus, healthy men and schizophrenia women exhibited
p
ce

extensive cerebral activations in the parietal and lateral frontal cortex and deactivations

in the medial prefrontal cortex. In contrast, healthy women and schizophrenia men
Ac

showed much more restricted activations and no significant deactivations [175]. In

other words, performance of mental rotation task was associated with greater

activations in male controls relative to male patients, but the opposite patter was

present in women. Since then we have tested additional participants and performed

new analyses. The differences in cerebral activations between the two groups of women

have diminished (consistently with their comparable performance on the mental

rotation task), but we have found a very different pattern of brain connectivity

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Page 32 of 59
(manuscript in preparation for publication, presented at MNS, 2015). Specifically, we

used the psychophysiological interaction method, and found that healthy women

demonstrated significant positive connectivity, and no negative connectivity, between

the dorsolateral PFC and regions in the occipital, parietal and frontal lobes, as well as

t
cingulate cortex. In contrast, no positive connectivity, but significant negative

ip
connectivity between the dorsolateral PFC and regions in the temporal lobe and

cr
cingulate cortex were observed in women with schizophrenia.

us
Another task, which we have investigated with great interest, is emotional

memory. The main findings have been presented at conferences and we are currently

an
reanalyzing the data with a greater number of participants, examining also functional

connectivity. In a nutshell, up to this point we have analyzed data from 40

M
schizophrenia outpatients (20 women) and 40 controls (20 women) who performed a

simple emotional memory task during fMRI sessions. The first part of the test consisted
d

of incidental encoding of emotionally positive, negative and neutral images. This was
te

followed by a 15 minutes of an unrelated distractor task and finally the test of emotional

memory where participants were presented again with pictures, half of which were old
p
ce

(from the incidental encoding portion of the procedure) and half of which were new. As

expected, schizophrenia patients performed less accurately in identifying old/new

Ac

images, but there were no sex differences in patients or in controls. The sex-specific

comparisons of the fMRI data revealed that women with schizophrenia showed less

activations compared to control women in an extensive network of brain regions that

included cortical and subcortical limbic structures. In contrast, men with schizophrenia

showed greater brain activations compared with control men in regions associated with

emotional processing as well as those implicated more generally in episodic memory.

We must clarify that in this case, the sex-specific effects were present due to significant

33
Page 33 of 59
sex differences in the control participants (greater activations in women than in men

across conditions), but not in patients. This suggests a diminished normal sexual

dimorphism in schizophrenia during emotional memory, but more studies are needed to

confirm these findings.

t
Although stimulating, there is a caveat with most fMRI studies of schizophrenia:

ip
the results cannot be generalized to all patients. The functional neuroimaging studies

cr
include typically highly functioning individuals who are willing to undergo the scanning

us
procedure and who can perform the task well enough to produce meaningful data.

Thus, it remains to be determined if we would find the same pattern of results with

an
more severely affected patients. Moreover, there could be multiple reasons for the

observed effects. The functional neuroimaging explanations trying to account for

M
differences between clinical populations and controls often argue for some kind of

‘compensatory mechanisms’, ‘different neurocognitive strategies’, or ‘brain mis-

d

wiring’/‘differences in connectivity’ in patients versus controls. However, what

te

contributes to this ‘mis-wiring’ or atypical ‘functional connectivity’ is unclear. Because in

this review we are considering differences between men and women, the two sets of
p
ce

relevant factors are those related to biological sex differences, such as sex steroid

hormones, as well as those related to psychosocial gender differences, such as gender

Ac

role and identity. These are discussed in subsequent sections, though the available data

are scarce.

7. Sex steroid hormones and neurocognitive function in schizophrenia

Sex steroid hormones have been shown to influence cognitive capacities in the

general population. For example, performance and cerebral function associated with

34
Page 34 of 59
visuo-spatial abilities have been related to levels of testosterone in men, with an overall

positive correlation or an inverted-U shape function [200-202], while performance and

cerebral activations associated with language and verbal memory tasks have been

positively correlated with levels of estradiol in women [203-205]. Some studies have

t
also observed negative correlations between estradiol and visospatial abilities in

ip
women [206]. Sex steroid hormones have been also implicated in the pathophysiology

cr
of schizophrenia [58, 207-209].

us
Our group has attempted to elucidate relationships between hormonal levels and

cerebral activations during cognitive processing in schizophrenia patients, but we have

an
been only partly successful; other protocols and techniques are needed to refine this

issue. In the study of mental rotation we have found significant correlations between
M
brain activations and testosterone levels in healthy men and surprisingly also in

schizophrenia women, but not in healthy women or in schizophrenia men [200]. The
d

finding in healthy males was consistent with other neuroimaging studies [202], while
te

the finding in female patients was somewhat supportive of the study by Bergemann and

associates (2008) who reported association between testosterone and spatial ability in
p
ce

schizophrenia women [210]. The role of testosterone in cognitive function in

schizophrenia has been also investigated more recently by Moore and colleagues (2013)
Ac

who tested exclusively males and found that higher circulating testosterone levels were

associated with better performance on verbal memory, processing speed, and working

memory in patients [211]. This might be a good time to remind the reader that

testosterone is converted to estradiol by aromatase, which is found in the gonads as well

as the brain. Therefore, while evaluating the effects of testosterone on neurocognition,

one cannot exclude the involvement of estradiol, unless both hormones have been

measured and correlated with a given function. In a different study of testosterone and

35
Page 35 of 59
other hormones, Halari and collegues (2004) found that high progesterone predicted

poorer performance and high testosterone predicted better performance on the spatial

memory in women, while higher cortisol levels were associated with poor cognitive

processing in men with schizophrenia [212]. In comparison, our study of progesterone

t
showed a positive correlation between progesterone levels and brain activations during

ip
processing of emotionally charged images in both healthy and schizophrenia men, but

cr
no significant relationship was revealed in women [213]. It has to be mentioned that in

us
all of these and subsequently discussed studies, it is uncertain how well the peripheral

hormonal levels correlate with brain levels.

an
In one of our studies concerned specifically with female patients, we investigated
M
cerebral function associated with processing of emotional stimuli across the menstrual

cycle [214]. We have found an interesting interaction between the diagnostic group and
d

phase of the menstrual cycle during exposure to the negatively charged images. Patients
te

showed relatively less activation than controls during the luteal phase (characterized by

a low estradiol to progesterone ratio), but no between-group differences during the

p
ce

follicular phase (characterized by a high estradiol to progesterone ratio). This effect was

apparent due to greater activations during the luteal relative to the follicular phase in
Ac

healthy women, but lack of increased reactivity to aversive information in women with

schizophrenia [214]. A few other studies have tried linking estradiol with cognitive

function in schizophrenia. For example, Thompson et al. (2000) have found that female

patients, similarly to healthy females, performed better on spatial tasks when their

levels of estradiol were diminished [215]. In contrast, Hoff et al. (2001) have found that

estrogen levels were correlated positively with better global cognitive function

including spatial memory and perceptual-motor speed [216].

36
Page 36 of 59
 To complicate the matter further, sex steroid hormones play an important

organizational role in terms of masculinization or feminization of the brain. This

process starts during fetal development and is mediated by two peaks of elevated levels

t
of testosterone in boys and the absence of such peaks in girls, laying down a foundation

ip
for neural sex differences [217]. In order for these differences to be fully expressed,

cr
rising sex steroid levels during puberty (i.e., testosterone in boys and estradiol in girls)

us
‘activate’ the circuits established during early neurodevelopment. It should be noted

however, that there are at present many additional candidate genes that may play a role

an
in sexual differentiation of the brain without the involvement of hormones [218].

Moreover, there is also evidence suggesting that gender role and identity contribute to
M
the differential brain function and structure [219-221]. As already mentioned in the

opening paragraphs of this review, it is believed that schizophrenia has

d

neurodevelopmental origins that reach 2nd and 3rd trimester of the fetal development,
te

which coincides with sexual differentiation of the brain. It is therefore possible that

some differences in the expression of schizophrenia between men and women are due
p
ce

to a hormonal ‘malfunction’ in utero, which would affects male and female brains

differently. Indeed there have been some attempts to examine this possibility. Thus, a
Ac

few studies have examined the ratio of the second to forth digit length (2D:4D), which is

believed to be an estimator of the prenatal hormonal levels. Specifically, lower 2D:4D

are believed to reflect a more masculine pattern with higher fetal testosterone in

relation to fetal estrodiol [222]. The results of studies in schizophrenia patients have

shown a feminized pattern in male patients [223-224], a masculinized pattern in female

patients [225] or no effect [226-227]. Despite this variability, it is conceivable that

schizophrenia (or a schizophrenia subtype) may be associated with an abnormality in

37
Page 37 of 59
prenatal circulating testosterone. This supposition is strengthen by findings of a

disturbed 2D:4D sexual dimorphism in individuals with schizotypal personality disorder

[227-228]. Another line of evidence associating schizophrenia with early hormonal

influences, comes from studies of Klinefelter’s syndrome, which is characterised by an

t
additional X chromosome, leading to the 47,XXY karyotype. This syndrome results in a

ip
variety of physical and cognitive deficits, including androgen deficiency and infertility,

cr
as well as impairments in verbal skills and social dysfunction [229]. In addition, a few

us
studies have associated the condition with psychiatric disorders, especially

schizophrenia (e.g., [230-231]

an
All of the studies mentioned in the present section add substantial complexity to
M
our discussion of sex differences in neurocognition in schizophrenia, pointing out that

some of the sex-specific and sex-dependent effects might be influenced by a current

d

hormonal status of female and male patients (e.g., menstrual cycle phase in women,
te

reproductive stage in both sexes), as well as by the early hormonal effects. Clearly more

studies are needed in this area. Another factor that is important to consider is gender of
p
ce

tested individuals.
Ac

8. Gender and neurocognitive function in schizophrenia

The question of gender role socialization, gender role adherence and gender

identity in schizophrenia, remains largely unexamined despite the fact that gender

identity problems have been proposed to play a significant role in the diathesis-stress

theory of the disorder almost 40 years ago [232]. As mentioned already in the opening

paragraph, several authors identify sex and gender as two independent realms with ‘sex’

38
Page 38 of 59
referring to the biological and physical characteristics, while ‘gender’ being related to

masculine or feminine traits, behaviors and beliefs considered to be appropriate for men

and women in a given culture [233]. Some of the earliest studies reported reversed

gender role and identity in patients with schizophrenia [234-236]. A more recent report

t
by Sajatovic and colleagues (2005) partially supports these early findings, as the authors

ip
found that patients with schizophrenia experience their gender identity differently from

cr
what is expected by their cultural norms. Specifically, both men and women with

us
schizophrenia endorsed traditionally male sex role statements to a lower extent than

normative expectations for their respective sex [237]. In other words, both men and

an
women with schizophrenia were less masculine that man and women in the general

population. In our studies we have found a similar effect using Bem Sex Role Inventory
M
[237] (unpublished observation).

In terms of neurocognitive function, Lewine (2004) has investigated a

d

contribution of sex and gender to clinical expression and neuropsychological

te

performance in schizophrenia and schizoaffective patients. Results revealed that sex,

but not gender, was a significant predictor of age at first hospitalization, even when
p
ce

controlling for illness severity. In comparison, the cognitive performance was

influenced by both sex and gender, such that being female predicted higher scores on
Ac

administered test, while more frequent endorsement of female typical social roles

predicted better neuropsychological functioning regardless of sex [238]. Similar results

were obtained in a subsequent study, in which Lewine and colleagues (2006) examined

sex and gender effects on seven domains of neuropsychological functioning among 197

schizophrenia/schizoaffective patients and 94 healthy individuals. The researchers

found that feminine participants, independent of sex and diagnosis, performed better

than masculine participants on all neurocognitive tests with the exception of executive

39
Page 39 of 59
function and attention [239]. The two exceptions underlined specificity of the gender

effect and showed that sex and gender should be investigated independently. In a

different study, which tackled gender-related questions, Parrott and Lewine (2005)

evaluated a relationship between parental socioeconomic status and clinical

t
manifestation of schizophrenia/schizoaffective disorder in men and women, and found

ip
some intriguing results. Namely, higher parental socioeconomic status was associated

cr
with decreased symptom severity in women and with increased symptom severity in

us
men. The authors suggested that the high socioeconomic status of origin may serve as a

significant source of stress for men, but not for women, predisposed to schizophrenia

an
[240]. Although scarce, this literature emphasizes the importance of considering both

biological sex and psychosocial gender in studies of cognitive function in schizophrenia.

M
9. Conclusions
d
te

Although variable and not free from limitations, the presented literature on

neuroanatomical and neurocognitive sex/gender differences in schizophrenia has led us

p
ce

to discern a few emerging patterns of results. First, in terms of neuroanatomical

differences we see that many studies of gross morphology show greater reductions in
Ac

the total brain volume, VBR, frontal and temporal lobe, in men than in women with

schizophrenia [110, 118]. These findings appear to be especially pronounced in

chronically ill patients and are consistent with the direction of normal sexual

dimorphism [142]. In comparison, studies of brain asymmetry, GI and corticolimbic

system, suggest diminished or reversed normal sexual dimorphism in schizophrenia

[143, 151]. Second, consistently with the neuroanatomical sex differences, the cognitive

behavioral studies reveal that in chronic schizophrenia, men present with more

40
Page 40 of 59
cognitive deficits than women [159-160]. Furthermore, while studies of cognitive

processes mediated by the lateral frontal cortex and fronto-parietal network, tend to

show typical sexual dimorphism [174, 195], the studies of processes mediated by the

corticolimbic system, more frequently show reversal of normal sexual dimorphisms

t
[176-177, 191]. Finally, the cognitive neuroimaging studies support a disturbance of

ip
normal sexual dimorphism in schizophrenia, but they are scarce and difficult to

cr
interpret [175, 196, 241].

us
While discussing differences between men and women, it is important to

consider a relative contribution of biological sex and psychosocial gender to the

an
observed effects. These variables have been examined only in a few studies, which

suggest a potential involvement of sex steroid hormones [174, 200, 211], as well as
M
gender role and identity [238-239], in observed differences in the neurocognitive

function between men and women with schizophrenia. A whole range of other factors
d

potentially contributing to neurocognitive sex differences in schizophrenia cannot be

te

excluded. These include differences in genetic and epigenetic mechanisms, different

severity and types of perinatal complications, as well as exposure to viruses and

p
ce

environmental toxins that could affect men and women predisposed to schizophrenia

differently.
Ac

On one hand we may be disconcerted by the variability in the available

neurocognitive studies in schizophrenia. On the other hand, it is not that surprising

given the heterogeneity of clinical expression, course of illness and response to

treatment in schizophrenia. Another important factor, which contributes to

heterogeneity of results and obscures straightforward conclusions is the fact that only a

few of the discussed studies assessed never-medicated patients, while the rest included

populations treated with a wide range of drugs with potentially multiple effects on brain

41
Page 41 of 59
and cognition. In addition, it is possible, and indeed very likely given the fact that

virtually all antipsychotic meditations act via dopaminergic blockade [242] and that the

dopaminergic system is sexually dimorphic [243], that even identical compounds exert

somewhat different effects on the brains of men and women.

t
ip
Finally, we are not certain if we are dealing with one distinct disorder or with

cr
multiple schizophrenias with different genetic and environmental etiologies [238-239].

us
Ideally, elucidation of various etiological subtypes of schizophrenia would be

incorporated in the sex and gender differences studies, but it remains elusive. At this

an
point it is accepted that, similarly to other psychiatric disorders, schizophrenia results

from a combination of biopsychosocial insults, where individual cases might be

M
differentially affected by biological, psychological or social factors. It is therefore

possible that sex and gender differences are most pronounces in cases provoked mainly
d

by negative environmental/social events, while cases brought about mainly by genetic

te

factors are characterized by less pronounces sexual dimorphism (or vice versa, we

simply do not know).

p
ce

Future studies will need to tackle these questions in a more controlled and

systematic manner; there is a great deal of work ahead.

Ac

42
Page 42 of 59
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 Diagnosis (N) Patients Age (mean Controls Age (mean Brain region examined Approach Main findings
N (M:F) & SD) N (M:F) & SD)

29 FEP 21:8 22.0 (5.1) 12:10 24.7 (6.4) Thalamus MRI male FEP but not females
26 SZ a single rater showed significantly smaller right a
2 SZA manual volumetric internal capsule volumes compared
1 psychosis not measures volunteers
otherwise
specified

sen et al SZ (52) 36:16 30.1 (9.6) 48:42 27.43 Total brain volume MRI male SZ had brain tissue deficit in a
(10.33) cerebrospinal fluid (CSF), automated cerebral regions.
and CSF within the volumetric measures
ventricular system. using locally female SZ had deficit only in
developed software
Regional measures:
frontal, temporal, parietal,
and occipital

t
lobes and the cerebellum

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sen et al SZ (54) 36:18 M=32.46 28:19 M 32.93 Ventricular volume MRI Most of the increased ventricular siz
(8.59) (9.25) Manual in the male patients.
F=35.39 F 36.63 measurement
(10.75) (12.67) Significantly smaller thalamus i

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patients

al 1997. SZP (20) 11:9 M 37.1 (4.7) 10:10 M 38.2 (9.3) Total brain volume, left MRI Male patients showed less asymme
F 38.2 (5.6) F 3.1 (6.5) and right hemisphere, and combined control group, while the female patie

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left and right superior automated and significantly more asymmetry.
temporal gyri. manual
segmentation The male patient had smaller
gyri than the control group.

No evidence of total brain volume

an
SZ (70) 40:30 28.7 (6.9) 34:47 26.4 (6.7) Gray and MRI Reduction in the dorsolateral
white matter volumes of manual area in men (9%) and women (11%
the dorsolateral, segmentation dorsomedial area only in men (9%),
dorsomedial, orbital regions only in women (23%
orbitolateral, and lateral and medial, respectively).
M
orbitomedial prefrontal
cortex SZ associated with reduced gray
matter volume in prefrontal cortex, w
both men and women in the dorsola

The effects are moderated by sex fo

d

dorsomedial and orbital regions and

to symptom severity and cognit
te

SZ (100) 58:42 29.2 (7.3) 51:59 26.1 (6.3) Gray and white matter MRI Hippocampal volume reduced
volumes manual in women
of temporolimbic segmentation
(hippocampus and Amygdala decreased volume i
p

amygdala) and women had increased volume.

neocortical regions
(superior temporal gyrus temporal pole: more decreased gray
ce

and temporal men (10%) than women (8.5%).

pole)
Superior temporal gyrus, decrease

SZ (108), SZ M 32.4 F 59:91 M 31.5 Global MRI SZ males had significantly more mo
Ac

SZA (20), MDD (82:26) 33.9 F 35.2 brain images anomalies especially of the lateral v
(27), BPD (20) SZA M 39.4 F evaluated by than healthy male volunteers; n
(7:13) 39.6 neuroradiologists SZ women
MDD M 39.3 blind to diagnosis
(7:20) F41.4
BPD M 32.6 F
(5:15) 39.7

SZ (80) 40:40 M 28.8 (7.3) 40:40 M 28.4 (7.1) Ventricles, CSF and whole MRI Male patients significantly larger ven
F 27.4 (7.8) F 27.8 (7.6) brain volumes automated male controls, female patients no si
volumetric measures enlargement in comparison with
of major brain
regions

SZ 36:23 M 32.66 19:18 M 34.26 Temporal lobe: superior MRI Left temporal lobe volume was s
(5.53) (6.65) temporal gyrus, Automated smaller in male patients than in mal
F37.31 F 33.33 amygdala/hippocampal volumetric measure comparison subjects
(5.09) (8.02) complex, temporal lobe Female patients and female compar
volume; prefrontal cortex subjects demonstrated no significan
and caudate in temporal lobe volume

There were no statistically significan

interactions for the superior tempora
amygdala/hippocampal complex, or
58 regions
comparison
Page 58 of 59
SZ 70:32 87 Lateral and third MRI no significant sex by diagnosis effec
ventricles, thalamus, regions of interest the regions of interest
hippocampus, and volume were
M: males, F: females, SZ: schizophrenia, FES: First episode schizophrenia, MRI: magnetic resonance imaging, SZT:
schizotypal disorder, BPD: Bipolar disorder, SZA: schizoaffective disorder, FEP: first episode psychosis, SZP: paranoid
schizophrenia, MDD: major depressive disorder, ROI: region of interest, SZU: schizophrenia undifferentiated, AOSZ: adolescent
onset schizophrenia, EOSZ: early onset schizophrenia

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