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Schizophrenia and sex differences in emotional processing Marion Rita Margaretha Scholten
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Page 1: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Schizophrenia and sex differences

in emotional processing

Marion Rita Margaretha Scholten

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The studies described in this thesis were performed at the Department of Psychiatry, University Medical Center Utrecht

ISBN: 13 978-90-393-4486-6Copyright © 2007 Marion ScholtenPrinted in the Netherlands by: Ridderprint Offsetdrukkerij B.V.Lay-out: Kitty Hieltjes INDIGO Grafie Media DienstenCover: Renée de Zwart

Alle rechten voorbehouden. Niets uit deze uitgave mag worden verveel- voudigd, opgeslagen in een automatisch gegevensbestand, of openbaar gemaakt, in enige vorm of op enige wijze, hetzij elektronisch, mechanisch, door fotokopie-en, opname of enigerlei andere manier, zonder voorafgaande schriftelijke toe-stemming van de auteur.

All rights reserved. No part of this publication may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or informa-tion storage and retrieval) without the prior written permission of the author.

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Schizophrenia and sex differences

in emotional processing

Schizofrenie en sekseverschillen in emotionele informatieverwerking(met een samenvatting in het Nederlands)

Proefschriftter verkrijging van de graad van doctor aan de Universiteit Utrecht

op gezag van de rector magnificus prof. dr. W.H. Gispeningevolge het besluit van het College voor Promoties

in het openbaar te verdedigenop maandag 23 april 2007 des middags te 2.30 uur

doorMarion Rita Margaretha Scholten

geboren op 4 maart 1954 te Palembang, Indonesië

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Promotores: Prof. dr. R.S. Kahn Prof. dr. A. Aleman

Co-promotor: Dr. J. van Honk

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Contents

Chapter One: General Introduction 7

Chapter Two: Emotion recognition Part One: Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67.

Part Two: The processing of emotional prosody and semantics in schizophrenia: relationship to gender and IQ. 41

Chapter Three: MemorySchizophrenia and sex differences in the simultaneous andsequential processing of language and emotion. 63

Chapter Four: Behavioral Inhibition and ActivationBehavioral Inhibition System (BIS), Behavioral Activation System (BAS) and schizophrenia: relationship with psychopathology and physiology.Journal of Psychiatric Research, 2006;40:638-645. 83

Chapter Five: Empathy and social perceptionSchizophrenia and sex differences in Empathizing-Systemizing abilities and perception of social interaction. 103

Chapter Six: General discussion 119

Nederlandse samenvatting 140

Dankwoord 146

Curriculum Vitae 148

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1General Introduction

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Chapter one 9

Sex differences and schizophrenia.Schizophrenia is a chronic psychiatric disorder that is usually characterized by a progressive decline in functioning. One of the most consistent findings in schizo-phrenia research that dates back into the 19th century, is that numerous studies have noted sex differences in course and outcome of the disorder (Häfner et al., 1994; Leung & Chue, 2000). An important difference is the age at onset, which is several years later in women (25-32 years) than in men (18-25 years). Since women are older than men at the time of their first psychosis, they are able to achieve a higher level of social functioning prior to the development of the illness and to hold significantly more roles concerning partnership, living conditions, in-come, and occupation than men at the time of onset (Häfner et al., 1999a,b). During the first decade following onset, the severity of illness is less debilitating in women than in men. Female patients have briefer and fewer hospitalizations and a less severe course of illness with respect to mental status, social adapta-tion and occupational status (Angermeyer et al. 1990; Goldstein, 1988) although it worsens in subsequent years. Self-neglect, social withdrawal, social inattentive-ness and social maladjustment are more frequent in male patients with schizo-phrenia (Goldstein & Link, 1988; Häfner et al., 1994). Positive symptoms (e.g. delusions, hallucinations and disorganisation) are the same for both sexes and fall with age for both, negative symptoms (e.g. blunted affect, social withdraw-al, loss of interest, anergia, lack of self-care) increase with age. In female pa-tients, negative symptoms remain less severe across all ages (Gur et al., 1996). Part of the better outcome in women in the short and midterm may be explained by better pre-morbid functioning and later age at onset (Häfner et al., 1999a,b), a better compliance, better response to drug treatment (Salongkas, 1995), and less co-morbid substance abuse than in male patients.

Although the cause of sex differences in schizophrenia is not yet fully under-stood, differences between men and women in the pace of brain development (slower in men) and in asymmetry in brain structures (more lateralization in men), as regulated by prenatal effects of sex steroid hormones, have been hy-pothesized to influence vulnerability to, and manifestation of the illness (Collaer & Hines, 1995; Diamond, 1989; Geschwind & Galaburda, 1987). Thus sex differ-ences in schizophrenia may be the result of exaggeration or attenuation of dif-ferences in brain areas that are normally sexual dimorphic.

In healthy people, dimorphic brain functioning is supposed to underlie differ-ences in cognitive and emotional processing between the sexes. Widely report-ed domains of sexual dimorphic performance are for example perception (Hall, 1978, 1984; McClure, 2000) and expression (Brody & Hall, 1993; Kring & Gor-don, 1998) of emotion, social cue perception (Constanzo & Archer, 1989; No-wicki & Duke, 1994), empathic capacity (Baron-Cohen, 2002, 2004), and verbal processing (Halpern & LaMay, 2000; Kimura, 1999), all vital for social function-ing and better in women, and visuo-spatial processing, better in men (Linn & Pe-tersen, 1985; Roberts & Bell, 2003).

In research on schizophrenia, several studies have shown patients to be im-paired in emotional processing, and these difficulties were found to be associated

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10 General Introduction

with impoverished social skills (Hooker & Park, 2002; Mueser et al., 1996; Poole et al., 2000). Since male patients are more impaired in social functioning than female patients, this may in part be the result of the preservation of the female advantage in several domains of emotional processing. Therefore studying sex differences in emotional processing in schizophrenia may contribute to a better understanding of the differences between male and female patients in the clini-cal manifestation of the illness.

Emotional processing Emotional processing is a broad concept, which involves for example perception, appraisal, subjective experience and expression of emotions, but also encoding, storage and retrieval of emotional information, skills in social interaction and em-pathic abilities. Knowledge and understanding of the neurobiological basis under-lying emotional processing are still limited, but studies using lesion techniques in animals (Adolphs et al., 1994; Broks et al., 1998; Young et al., 1995, 1996) and functional imaging in humans (Morris et al., 1996, 1998; Schneider et al., 1997) have demonstrated that networks of different brain structures are implied. Phillips et al., (2003a,b) hypothesized two neural systems to form the basis of emotion perception: a ventral system, including the amygdala, insula, ventral striatum, ventral anterior cingulate gyrus, and prefrontal cortex, for the identification of the emotional significance of a stimulus, the production of affective states, and automatic regulation of emotional responses, and a dorsal system including the hippocampus, dorsal anterior cingulate gyrus, and prefrontal cortex responsible for the effortful regulation of affective states and subsequent behavior.

Schizophrenia has been associated with structural and functional abnormalities in both neural systems (Phillips et al., 2003a,b), and various domains of cogni-tive and emotional processing are known to be impaired in patients with schizo-phrenia. Deficits in performance on tasks of selective attention, working memory (Goldman-Rakic, 1994), and long-term memory (Barch, 2005; Goldberg et al., 2003), and in the perception, appraisal and expression of emotions (Edwards et al., 2002; Shayegan & Stahl, 2005) have been commonly reported. Impairment has been demonstrated in the recognition of facial affect (Edwards et al., 2001; Feinberg et al., 1986), affective prosody (Edwards et al., 2001), and social cues (Corrigan & Green, 1993). These deficits are stronger for the recognition of neg-ative affect (Edwards et al., 2002; Kohler et al., 2003; Mandal et al., 1998), such as fearful faces (Gaebel & Wölwer, 1992), and fearful vocalizations (Phillips et al., 1998). Furthermore, the identification of the emotional significance of a stimulus has been found to be impaired. For example, findings in patients with schizophre-nia suggest an enhanced amygdalar response to ambiguous stimuli, which may be misinterpreted as more emotive and more threatening (Blackwood et al., 2001). This tendency to interpret ambiguous stimuli as more threatening, might become a pathway to psychosis. In contrast, patients with schizophrenia have also been reported to judge untrustworthy faces to be more approachable and trustworthy

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Chapter one 11

than controls did (Adolphs et al., 1998), which may enhance the risk for abuse that has been observed in patients with schizophrenia (Brekke et al., 2001).

Deficits in cognitive and emotional processing in schizophrenia may in part be accounted for by amygdalar and hippocampal dysfunction (Benes & Beretta, 2000; Gur et al., 2002; Heckers & Konradi, 2002; Phillips et al, 1999). Numer-ous studies have shown that these regions are important for the identification of visual (Adolphs et al., 1994; Phelps & Anderson, 1997) and auditory stimuli (especially fear) (Phillips et al., 1998), the memory of emotional information, in particular the appraisal and encoding of information (Cahill et al., 1996; Canli et al., 2000), the modulation of vigilance and attention to emotionally salient infor-mation (Davis & Whalen, 2001) and the production of emotional states and be-haviors (Morris et al., 1998; Reiman et al., 1997; Whalen et al., 1998). Indeed, volume decreases up to 6% in both brain structures have been observed in pa-tients with schizophrenia (Seidman et al., 2003; Wright et al., 2000).

Besides impaired recognition and appraisal of emotions, schizophrenic patients show impaired expression of emotions (Berenbaum & Oltmans, 1992; Kring et al., 1994), as reflected in negative symptoms like flattening of affect, emotional withdrawal or affective unresponsiveness (Kay & Lindenmayer, 1987). Negative symptoms and psychomotor poverty have been associated with structural and functional abnormalities in dorsolateral prefrontal cortex and dorsal anterior cin-gulate gyrus (Heckers et al., 1999; Liddle & Morris, 1991), regions implicated in the regulation of affective states and emotional behavior (Phillips et al., 2003,a,b). Since facial expressions and ‘body language’ are important communication chan-nels of feelings, the tendency to exhibit limited facial emotions and gestures will have pronounced negative effects upon the quality of social interactions.

Empathic capacity, or the ability to recognize and understand emotions and mental states of other persons and to respond to these with an appropriate af-fect (Blair et al., 2005), has been found to be lower in patients with schizophrenia compared to controls. Recent investigations have shown that higher (self report-ed) empathy is positively correlated with higher facial mimicry, or the imitation of facial emotions (Sonnby-Borgstrom, 2002). Mimicry has been suggested to be a precursor of empathy, and to underlie the ability to learn vicariously by simulat-ing another person’s state of mind within one’s own mind. In animal studies mir-ror neurons, responding equally to the perception and the execution of the same action, have been postulated to be a possible neural substrate of affect simulation (Iacoboni, 2005; di Pellegrino et al., 1992). In human subjects functional Magnet-ic Resonance Imaging (fMRI) studies have shown a network of brain structures that is jointly activated during the observation and the execution of movement (superior temporal sulcus, posterior inferior frontal gyrus, pre-motor areas, and rostral parietal lobule; Decety et al., 2002; Iacoboni et al, 1999, 2005). Among these regions were brain areas (the amygdala and the insula), known to be in-volved in facial affect recognition (Adolphs, 2003; Carr et al., 2003). This find-ing suggests that empathy may be rooted in automatic joint activation of areas implicated in affect and action representation (Gallese, 2003). In patients with

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12 General Introduction

schizophrenia empathic abilities will be hampered by deficits in recognition, ap-praisal and expression of emotions.

In summary, patients with schizophrenia show impairment in various domains of emotional processing, while there is accumulating evidence that the ability to accurately recognize emotions and intentions displayed by others, and to express own emotions in a proper way, is related to better social competence and out-come (Mueser et al., 1996).

Sex differences in emotional processingIn healthy controls, sex differences have been reported in perception and expres-sion of emotions. Women outperform men in the recognition of emotions in facial expressions, gestures and voices, and are more sensitive to emotional cues in themselves and others (Hall, 1978, 1984; McClure, 2000). Although this greater sensitivity has clear advantages in interpersonal contacts, it may also contribute to the finding that women are more prone to developing symptoms of anxiety and depression and show a stronger defensive orientation, with a primary dis-position to avoid danger (Breslau et al., 1997; Gater et al., 1998). This is con-sistent with findings on approach-withdrawal related behavior, assessed with the Behavioral Inhibition- Behavioral Activation scales (Carver & White, 1994) indi-cating that women show higher scores on Behavioral Inhibition than men, and are more sensitive to threat and punishment (Leone, 2001).

Regarding the expression of emotions women have been found to be more emotional expressive than men (Brody & Hall, 1993; Kring & Gordon, 1998), while men, in contrast, show higher physiological arousal in the electrodermal system, suggesting that men and women might primarily involve in different response systems (Lang et al., 1993).

In addition, women show higher scores than men in empathic capacities (Bar-on-Cohen, 2003, 2005). This may in part be associated with better recognition and expression of emotions in women, and may be influenced by different neu-ro-endocrine systems which have been hypothesized to play an important role in (sex differences in) empathy and pro-social behaviors (Young & Wang, 2004). For example, recent research demonstrated that high testosterone levels are related to less engagement in empathic behaviors (Baron-Cohen, 2002).

Taken together, women outperform men in a range of emotional processing abilities. Since better skills in emotional processing have been associated with a higher level of social functioning, preservation of this higher level might provide female patients with schizophrenia an advantage in social skills in the illness.

The objectives of this thesisThe main aim of this thesis is to examine whether sex differences in emotional processing, favoring women, are preserved in schizophrenia. To this end we as-sessed four groups of participants (male and female patients and male and fe-male controls) with a number of tasks in several domains of emotion processing.

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Chapter one 13

Since early age at onset and severe negative symptoms are correlated with more severe deficits in emotional processing, care was taken to avoid confounding ef-fects of symptom severity. Although female patients generally present at a later age of onset and with less severe negative symptoms than male patients, in this study male and female patients were carefully matched on age of onset, severi-ty of symptoms and dosage of medication.

Outline of the thesisChapter two describes two studies on emotion recognition (facial affect recog-nition and affect recognition in speech), and examines if the female advantage in emotion recognition has been preserved in schizophrenia.

However, daily life functioning rarely implies doing one thing at a time, such as emotion recognition, but requires multitasking. In order to study differences in emotional processing between men and women in a more ‘real-world’ situation, participants were assessed with two different working memory tasks that require the concurrent processing of language and emotion, and with a long-term mem-ory task (Chapter three).

The first working memory task measures sensitivity to interference in a dual task paradigm, the other working memory task measures the capacity to maintain and manipulate emotional and verbal information. Female patients were expect-ed to outperform male patients on both emotional working memory tasks, simul-taneously and sequentially processing language and emotion. On the long-term memory task, pictures with positive, negative and neutral content were shown. Positive emotions were expected to be recalled better than negative or neutral pictures (Danion et al., 2003). Because there is evidence that the emotional va-lence of stimuli may have different effects on memory in men and women (Lang, 1998), for this study we predicted female patients to outperform male patients in recognizing pictures with a negative content, and male patients to excel in rec-ognizing pictures with a positive content.

Chapter four consists of an analysis of the results on the Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS) questionnaires (Carver & White, 1994) in relation to psycho-physiological measures (Heart Rate (HR) and Heart Rate Variability (HRV)) and psychopathology in schizophrenia. In healthy controls, women have been found to show higher sensitivity on the BIS (Jorm, 1999; Leone, 2001), and more internalizing problems than men (Rosenfield, 2000), therefore we also expected female patients with schizophrenia to be more sensi-tive to threat (i.e., elevated BIS scores) than male patients. Since increased HR and decreased HRV have been shown to correlate with inhibited behavior (Ka-gan et al., 1987; Reznick et al., 1986) we expected high BIS sensitivity to corre-late with high scores on average heart rate (HR), and with low scores on heart rate variability (HRV).

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14 General Introduction

Regarding the BAS, excessive dopaminergic transmission, as has been suggest-ed to underlie psychotic (positive) symptoms and increased emotional reactivity in schizophrenia (Aleman & Kahn, 2005), may result in over-attribution of meaning to otherwise irrelevant cues. In contrast, reduced dopamine receptor sensitivity in the striatum, increased by neuroleptics, is associated with negative symptoms (avolition, apathy, affective flattening) (Heinz et al., 1998) and may reduce mo-tivational and emotional responses to reward-indicating situations (Robbins & Everitt, 1996; Schultz et al., 1997). Therefore on the BAS higher sensitivity to reward (BAS) was predicted to correspond to high levels of positive symptoms, and lower sensitivity to reward to high levels of negative symptoms.

Chapter five examines if the female advantage in empathic abilities, assessed with the Empathizing-Systemizing questionnaires (Baron-Cohen, 1999), and in perception of social interaction, assessed with a novel non-verbal social percep-tion interaction task, is preserved in patients with schizophrenia.

In Chapter six the most important findings are summarized and the theoretical and practical implications are discussed

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Chapter one 15

ReferencesAdolphs R, Tranel D, Damasio H, Damasio A. Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 1994;372:669-672.

Adolphs R, Tranel D, Damasio AR. The human amygdala in social judgment. Nature. 1998;393(6684):470-4. Comment in: Nature 1998;393(6684):417-418.

Adolphs R. Cognitive neuroscience of human social behavior. Nature Reviews Neuroscience 2003;4(3):165-178.

Aleman A, Kahn RS. Strange feelings: do amygdala abnormalities dysregulate the emotional brain in schizophrenia? Progress in Neurobiology 2005;77(5):283-298.

Angermeyer MC, Kuhn L. Gender differences in age at onset of schizophrenia. An overview. Eur Arch Psychiatry Neurol Sci 1988;237(6):351-364.

Barch DM. The cognitive neuroscience of schizophrenia. Annu Rev Clin Psychol 2005;1:321-353.

Baron-Cohen S, Jolliffe T, Mortimore C, Robertson M. Another advanced test of theory of mind: evidence from very high functioning adults with autism or Asperger Syndrome. J Child Psychol Psychiatry 1997;38:813-823.

Baron-Cohen S, Ring H, Wheelwright S, et al. Social intelligence in the normal and the autistic brain: an fMRI study. Eur J Neurosci 1999;11:1891-1898.

Baron-Cohen S. The extreme male brain theory of autism. Trends Cogn Sci 2002;6:248-254.

Baron-Cohen S, Richler J, Bisarya D, Gurunathan N, Wheelwright S. The systemizing quotient: an investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences. Phil Trans R Soc Lond 2003;358:361-374.

Baron-Cohen S, Wheelwright S. The empathy quotient: an investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences. J Autism Dev Disord 2004;34(2):163-175.

Baron-Cohen S, Knickmeyer RC, Belmonte MK. Sex differences in the brain: implications for explaining autism. Science 2005;310(5749):819-823.Comment in: Science 2006;311(5763):952;author reply 952.

Blackwood NJ, Howard RJ, Bentall RP, Murray RM. Cognitive neuropsychiatric models of persecutory delusions. Am J Psychiatry 2001;158(4):527-539.

Page 16: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

16 General Introduction

Benes FM, Berretta S. Amygdalo-entorhinal inputs to the hippocampal formation in relation to schizophrenia Ann N Y Acad Sci 2000;911:293-304.

Berenbaum H, Oltmanns TF. Emotional experience and expression in schizophrenia and depression. J Abnorm Psychol 1992;101(1):37-44.

Blair RJ. Responding to the emotions of others: dissociating forms of empathy through the study of typical and psychiatric populations. Conscious Cogn 2005;14(4):698-718.

Brekke JS, Prindle C, Bae SW, Long JD. Risks for individuals with schizophrenia who are living in the community. Psychiatr Serv 2001;52(10):1358-1366. Comment in: Psychiatr Serv 2001;52(10):1281.

Breslau N, Davis GC, Andreski P, Peterson EL, Schultz LR. Sex differences in posttraumatic stress disorder. Arch Gen Psychiatry 1997;54(11):1044-1048.

Brody LR, Hall JA. Gender and emotion. In: Lewis M & Haviland JM (Eds.). Handbook of emotions 1993;pp. 447-460. New York, NY:Guilford Press.

Broks P, Young AW, Maratos EJ, et al. Face processing impairments after encephalitis: amygdala damage and recognition of fear. Neuropsychologia 1998; 36(1):59-70.

Cahill L, Haier RJ, Fallon J, et al. Amygdala activity at encoding correlated with long-term, free recall of emotional information. Proc Natl Acad Sci USA 1996;93(15):8016-8021.

Canli T, Zhao Z, Brewer J, Gabrieli JD, Cahill L. Event-related activation in the human amygdala associates with later memory for individual emotional experience. J Neurosci 2000;20(19):RC99.

Carr L, Iacoboni M, Dubeau MC, Mazziotta JC, Lenzi GL. Neural mechanisms of empathy in humans: a relay from neural systems for imitation to limbic areas. Proc Natl Acad Sci USA 2003;100(9):5497-5502.

Carver CS, White TL. Behavioural Inhibition, Behavioural Activation, and Affective responses to Impending Reward and Punishment: The BIS/BAS scales. 1994;67:319-333.

Collaer ML, Hines M. Human behavioral sex differences: a role for gonadal hormones during early development? Psychological Bull 1995;118(1):55-107.

Corrigan P, Green M. Schizophrenic patients’ sensitivity to social cues: the role of abstraction. Am J Psychiatry 1993;150(4):589-594.

Costanzo M, Archer D. Interpreting the expressive behavior of others: The Interpersonal Perception Task. J Nonverbal Behavior 1989;13:225–245.

Page 17: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter one 17

Danion J-M, Kazes M, Huron C, Karchouni N. Do patients with schizophrenia consciously recollect emotional events better than neutral events? Am J Psychiatry 2003;160:1879-1881.

Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol Psychiatry 2001;6(1):13-34.

Decety J, Chaminade T, Grezes J, Meltzoff AN. A PET exploration of the neural mechanisms involved in reciprocal imitation. Neuroimage 2002;15(1):265-272.

Diamond MC. Sex and the cerebral cortex. Biol Psychiatry 1989;25:823-825.

Edwards J, Jackson HJ, Pattison PE. Emotion recognition via facial expression and affective prosody in schizophrenia: a methodological review. Clin Psychol Rev 2002;22:789-832. Erratum in: 2002, Clin Psychol Rev 22:1267-1285.

Edwards J, Pattison PE, Jackson HJ, Wales RJ. Facial affect and affective prosody recognition in first-episode schizophrenia. Schizophr Res 2001;48(2-3):235-253.

Feinberg TE, Rifkin A, Schaffer C, Walker E. Facial discrimination and emotional recognition in schizophrenia and affective disorders. Arch Gen Psychiatry 1986;43(3):276-279.

Gaebel W, Wolwer W. Facial expression and emotional face recognition in schizophrenia and depression. Eur Arch Psychiatry Clin Neurosci 1992;242(1):46-52.

Gallese V. The roots of empathy: the shared manifold hypothesis and the neural basis of intersubjectivity. Psychopathology 2003;36(4):171-180.

Gater R, Tansella M, Korten A, Tiemens BG, Mavreas VG, Olatawura MO. Sex Differences in the Prevalence and Detection of Depressive and Anxiety Disorders in General Health Care Settings. Arch Gen Psychiatry 1998;55:405-413.

Geschwind N, Galaburda AM. Cerebral lateralization: Biological mechanisms, associations and pathology. Cambridge, MA:MIT Press. 1987.

Goldberg T, David A, Gold J. Neurocognitive deficits in schizophrenia. In: Hirsch S, Weinberger D. (Eds.), Schizophrenia. Blackwell Science Ltd, 9600 Garsington Road, Oxford OX42DQ, UK, 2003, pp168-184.

Goldman-Rakic P. Working memory dysfunction in schizophrenia. J Neuropsychiat Clin Neurosc 1994;6:348-357.

Goldstein J, Link B. Gender and the expression of schizophrenia. J Psychiatr Res 1988;22: 141-155.

Page 18: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

18 General Introduction

Goldstein J. Gender differences in the course of schizophrenia. Am J Psychiatry 1988;145: 684-689.

Gur RE, Petty R, Turetsky B et al. Schizophrenia throughout life: sex differences in severity and profile of symptoms. Schizophr Res 1996;21:1-12.

Gur RE, McGrath C, Chan RM, et al. An fMRI study of facial emotion processing in patients with schizophrenia. Am J Psychiatry 2002;159(12):1992-1999.

Häfner H, Maurer K, Löffler W. The epidemiology of early schizophrenia. Influence of age and gender on onset and early course. British Journal of Psychiatry1994;164(suppl.23):29-38.

Häfner H, Maurer K, Löffler W. Onset and prodromal phase and determinants of the course. In: Gattaz WF and Häfner H (Eds.), Search for the Causes of Schizophrenia. Vol. IV. Balance of the Century, Springer, Berlin, Heidelberg, Steinkopff, Darmstadt, 1999a, pp.35–58.

Häfner H, Heiden W an der. The course of schizophrenia in the light of modern follow-up studies: the ABC and WHO studies. European Archives of Psychiatry and Clinical Neuroscience 1999b;249(Suppl 4):14-26.

Hall J. Gender effects in decoding nonverbal cues. Psychol Bull 1978;85:845-858.

Hall J A. Nonverbal sex differences: Communication accuracy and expressive style. Baltimore: Johns Hopkins University Press, 1984.

Halpern D, LaMay L. The smarter sex: A critical review of sex differences in intelligence. Educational Psychology Review 2000;12: 229-246.

Heckers S, Konradi C. Hippocampal neurons in schizophrenia J Neural Transm 2002;109(5-6):891-905.

Heckers S, Goff D, Schacter DL, Savage CR, Fischman AJ, Alpert NM, Rauch SL. Functional imaging of memory retrieval in deficit vs nondeficit schizophrenia. Arch Gen Psychiatry 1999;56(12):1117-1123.

Heinz A, Knable MB, Coppola R, Gorey JG, Jones DW, Lee KS et al. Psychomotor slowing, negative symptoms and dopamine receptor availability- an IBZM study in neuroleptic-treated and drug-free schizophrenic patients. Schizophr Res 1998;31:19-26.

Hooker C, Park S. Emotion processing and its relationship to social functioning in schizophrenia patients. Psychiatry Res 2002;112:41-50.

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Chapter one 19

Iacoboni M, Woods RP, Brass M, Bekkering H, Mazziotta JC, Rizzolatti G. Cortical mechanisms of human imitation. Science 1999;286(5449):2526-2528.

Iacoboni M, Molnar-Szakacs I, Gallese V, Buccino G, Mazziotta JC, Rizzolatti G. Grasping the intentions of others with one’s own mirror neuron system. PLoS Biol 2005 Mar;3(3):e79.

Jorm AF, Christensen H, Henderson AS, Jacomb PA, Korten AE, Rodgers B. Using the BIS/BAS scales to measure behavioural activation: Factor structure, validity and norms in a large community sample. Personality & Individual Differences 1999;26:49-58.

Kagan J, Reznick JS, Snidman N. The physiology and psychology of behavioral inhibition in children. Child Dev 1987;58(6):1459-1473.

Kay SR, Lindenmayer JP. Outcome predictors in acute schizophrenia. Prospective significance of background and clinical dimensions. J Nerv Ment Dis 1987;175(3):152-160.

Kimura D. Sex and cognition. The MIT Press, Cambridge MA 1999.

Kohler CG, Turner TH, Bilker WB, et al. Facial emotion recognition in schizophrenia: intensity effects and error pattern. Am J Psychiatry 2003;160:1768-1774.

Kring AM, Gordon AH. Sex differences in emotion: expression, experience, and physiology. J Pers Soc Psychol 1998;74(3):686-703.

Kring AM, Alpert M, Neale JM, Harvey PD. A multimethod, multichannel assessment of affective flattening in schizophrenia. Psychiatry Res 1994;54(2):211-222.

Lang PJ, Greenwald MK, Bradley MM, Hamm AO. Looking at pictures: affective, facial, visceral, and behavioral reactions. Psychophysiology 1993;30(3):261-273.

Lang P, Bradley M, Fitzsimmons J, et al. Emotional arousal and activation of the visual cortex: An fMRI analysis. Psychophysiology 1998;35:1-13.

Leone L, Perugini M, Bagozzi RP, Pierro A, Mannetti L. Construct validity and generalizability of the Carver-White Behavioural Inhibition System / Behavioural Activation System Scales. Eur J Personality 2001;15:373-390.

Leung A, Chue P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand 2000;(Suppl.)101:3-38.

Liddle PF, Morris DL. Schizophrenic syndromes and frontal lobe performance. Br J Psychiatry 1991 Mar;158:340-345.

Page 20: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

20 General Introduction

Linn MC, Petersen AC. Emergence and characterization of sex differences in spatial ability: a meta-analysis. Child Dev 1985;56(6):1479-1498.

Mandal MK, Pandey R, Prasad AB. Facial expressions of emotions and schizophrenia: a review. Schizophr Bull 1998;24(3):399-412.

McClure EB. A meta-analytic review of sex differences in facial expression processing and their development in infants, children, and adolescents. Psychol Bull 2000;126: 424-453.

Morris JS, Frith CD, Perrett DI, Rowland D, Young AW, Calder AJ, Dolan RJ. A differential neural response in the human amygdala to fearful and happy facial expressions. Nature 1996;383(6603):812-815.

Morris JS, Friston KJ, Buchel C, Frith CD, Young AW, Calder AJ, Dolan RJ. A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain 1998;121(Pt 1):47-57.

Mueser K, Doonan R, Penn D, et al. Emotion recognition and social competence in chronic schizophrenia. J Abnormal Psychol 1996;105:271-275.

Nowicki S, Duke MP. Individual differences in the nonverbal communication of affect: The Diagnostic Analysis of Nonverbal Accuracy Scale. J Nonverbal Behavior 1994;18:9–36.

di Pellegrino G, Fadiga L, Fogassi L, Gallese V, Rizzolatti G. Understanding motor events: a neurophysiological study. Exp Brain Res 1992;91(1):176-180.

Phelps EA, Anderson AK. Emotional memory: what does the amygdala do? Curr Biol 1997;7(5):R311-314.

Phillips ML, Young AW, Scott SK, et al. Neural responses to facial and vocal expressions of fear and disgust. Proc Biol Sci 1998;265(1408):1809-1817.

Phillips ML, Williams L, Senior C, et al. A differential neural response to threatening and non-threatening negative facial expressions in paranoid and non-paranoid schizophrenics. Psychiatry Res 1999;92(1):11-31.

Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biol Psychiatry 2003b ;54(5):504-514.

Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol Psychiatry 2003a ;54(5):515-528.

Poole JH, Tobias F, Vinogradow S. The functional relevance of affect recognition errors in schizophrenia. J Int Neuropsychol Soc 2000;6:649-658.

Page 21: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

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Reiman EM, Lane RD, Ahern GL, et al. Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 1997;154(7):918-925.

Reznick JS, Kagan J, Snidman N, Gersten M, Baak K, Rodenberg A. Inhibited and uninhibited children: a follow-up study. Child Dev 1986;57:660-680.

Robbins TW, Everitt BJ. Neurobehavioral mechanisms of reward and motivation. Curr Opinion Neurobiol 1996;6:228-236.

Roberts JE, Bell MA. Two- and three-dimensional mental rotation tasks lead to different parietal laterality for men and women. Int J of Psychophysiology 2003;50(3):235-246.

Rosenfield S. Gender and dimensions of the self: Implications for internalizing and externalizing behavior. In: Frank E. (Ed.), Gender and its effects on psychopathology. American Psychopathological Association Series. American Psychiatric Press, Washington, DC, 2000:23-36.

Salonkangas R. Gender and the use of neuroleptics in schizophrenia. Further testing of the oestrogen hypothesis. Schizophr Res 1995;16:7-16.

Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science 1997;275:1593-1599.

Schneider F, Grodd W, Weiss U, Klose U, Mayer KR, Nagele T, Gur RC. . Functional MRI reveals left amygdala activation during emotion. Psychiatry Res 1997;76(2-3):75-82.

Seidman LJ, Pantelis C, Keshavan MS, et al. A review and new report of medial temporal lobe dysfunction as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric family study of the parahippocampal gyrus. Schizophr Bull 2003;29(4):803-30. Comment in: Schizophr Bull 2003;29(4):845-9. Schizophr Bull 2003;29(4):851-8. Schizophr Bull 2003;29(4):859-65.

Shayegan DK, Stahl SM. Emotion processing, the amygdala, and outcome in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(5):840-845.

Sonnby-Borgstrom M. Automatic mimicry reactions as related to differences in emotional empathy. Scand J Psychol 2002;43(5):433-443.

Whalen PJ. Fear, vigilance and ambiguity: Initial neuroimaging studies of the human amygdala. Current directions in Psychological Science 1998;7(6):177-188.

Whittaker JF, Deakin JF, Tomenson B. Face processing in schizophrenia: defining the deficit. Psychol Med 2001;31(3):499-507.

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22 General Introduction

Wright I, Rabe-Hesketh S, Woodruff P, David A, Murray R, Bullmore E. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;157:16-25.

Young LJ, Wang Z. The neurobiology of pair bonding. Nature Neuroscience 2004; 7(10):1048-1054.

Young AW, Hellawell DJ, Van De Wal C, Johnson M. Facial expression processing after amygdalotomy. Neuropsychologia 1996;34(1):31-39.

Young AW, Aggleton JP, Hellawell DJ, Johnson M, Broks P, Hanley JR. Face processing impairments after amygdalotomy. Brain 1995;118:15-24.

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2Emotion recognition

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Part 1

Schizophrenia and processing of facial emotions: sex matters

Marion R.M. ScholtenAndré AlemanBarbara MontagneRené S. Kahn

Schizophrenia Research, 2005;78(1):61-67.

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28 Emotion recognition

AbstractThe aim of this study was to examine sex differences in emotion processing in patients with schizophrenia and control subjects. To this end, 53 patients with schizophrenia (28 men and 25 women), and 42 controls (21 men and 21 wom-en) were assessed with the use of a facial affect recognition morphing task. Ac-curacy and sensitivity scores were measured. Women performed better than men in labelling negative emotions. On the same task, patients performed worse than control subjects, irrespective of sex, although the largest degree of impairment was seen in male patients. In conclusion, emotion perception was disproportion-ally affected in men with schizophrenia relative to women. This may explain, in part, why women with schizophrenia are less impaired in social life than men suf-fering from this illness.

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1. Introduction Numerous studies in schizophrenia have noted higher risks (Aleman et al., 2003), earlier onset, poorer premorbid functioning, treatment response, course and out-come in men than in women (Castle et al., 1993; Goldstein et al., 2000; Häfner et al., 1994; Leung et al., 2000). Although the cause of these sex differences is not yet fully understood, oestrogen’s effect on the female brain has often been postulated to protect against (the early onset of) severe schizophrenia in women (Castle et al., 1995; Häfner et al., 1998; Seeman et Lang, 1990).

Emotional processing, particularly facial affect recognition, is known to be im-paired in schizophrenia (Edwards et al., 2002; Kohler et al., 2003; Mandal et al., 1998). This impairment has been shown to relate to social dysfunction (e.g. impov-erished interpersonal relations, limited community participation, bizarre behaviour and appearance (Mueser et al., 1996; Penn et al., 1996; Poole et al., 2000)).

In healthy people, sex differences are found in the ability to recognise emotions from faces, with women outperforming men (Hall, 1978, 1984). A meta-analy-sis by McClure (2000) also indicated a female advantage in accuracy at identify-ing facial expressions, which was more outspoken for negative emotions such as fear, disgust and sadness (Miura, 1993) than for positive emotions. Therefore, studying sex differences in emotional processing may contribute to a better un-derstanding of the differences between male and female patients in the clinical manifestation of schizophrenia.

In the present study, we hypothesised that the female advantage in facial af-fect recognition would be preserved in schizophrenia. That is, we expected fe-male patients with schizophrenia to outperform male patients on a task of facial emotion recognition. We were particularly interested in the recognition of nega-tive emotions, since negative emotions are known to be more difficult to identify than positive emotions (Ekman, 1982, 1999; Gosselin et al., 1995; Kirita & Endo, 1995), and because the recognition of negative emotions is known to be impaired in schizophrenia (Edwards et al., 2002; Mandal et al., 1998).

2. Method 2.1. ParticipantsFifty-three patients with schizophrenia (28 men, 25 women) and 42 controls (21 men, 21 women) participated in this study. To avoid effect of the menstrual cy-cle, all female participants were tested in the first 10 days of their cycle (start-ing from day 1 of menstruation). Psychiatric diagnosis was established via a structured interview (the Comprehensive Assessment of Symptoms and History, (CASH), Andreasen et al. 1992). Criteria for entry into the study were a diagno-sis of schizophrenia, no concomitant axis I disorder, and no medical or neuro-logical event or disorder that might affect brain function. In addition, all patients were administered the Positive And Negative Syndrome Scale (PANSS; Kay et al., 1986). With this structured interview positive and negative symptoms in schizo-phrenia, including their severity, were assessed. A physical examination with lab-oratory tests was performed by a physician at study entry. Patients were studied

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while clinically stable, without prominent positive symptoms at the time of test-ing. Most of them (n=42) were outpatients. Female (n=22) and male (n=24) patients were mainly diagnosed with schizophrenia, paranoid subtype. Only 1 fe-male patient and 3 male patients were diagnosed with a disorganized subtype, 1 male and 1 female patient with an undifferentiated subtype and 1 male patient with a catatonic subtype.

All patients were treated with atypical antipsychotic medications and none of them used co-medication, such as tranquillisers or antidepressants. Male and fe-male patients did not differ in number of hospitalisations, age at first psychosis and dosage of medication. Duration of illness showed a trend of women being ill longer than men (F = 3.2; p = 0.08).

The control subjects were volunteers from the Utrecht University Hospital or were recruited through an advertisement in newspapers. They were assessed with the SCID non-patient version (Sheehan et al., 1998) and had no history of any illness affecting brain function or a history of major psychiatric illness in first-degree relatives.

Patients and comparison subjects did not differ significantly in terms of age and education. Group characteristics of patients and controls are reported in Ta-ble 1.

After complete description of the study to the subjects, written informed con-sent was obtained. The study was approved by the Medical Ethical Committee of the University Medical Centre Utrecht.

2.2. Materials: Facial Affect Recognition Task A computer-generated program by Rowland & Perrett (1995), developed from al-gorithms, was used (ref.: Frigerio et al., 2002; Montagne et al., 2005). This pro-gram was devised to enable a real-time interactive morphing (gradual change) between two endpoint facial expressions of the same face, from 0% emotion (neutral face) to 100% emotion. The task was especially developed to measure accuracy, as well as sensitivity, when recognising facial emotional expressions. Stimuli for this test were based on 48 colour pictures from 4 actors, 2 men and 2 women, each mimicking 6 emotional expressions, in frontal (face view) and in profile (side view). To measure accuracy, these pictures were morphed (trans-formed) from neutral to a facial expression, by pressing a button. Subjects had to indicate which emotion (anger, happy, sadness, fear, surprise or disgust) they perceived. Then the face returned to a neutral expression. To measure sensitivi-ty (i.e. the intensity of the expression at which the emotion was identified), sub-jects were asked to indicate at which point they could first perceive the emotion in the face while they (again) changed the expression from 0% to 100% using the ‘<’ and ‘>’ buttons.Figure 1 shows an example of the stimuli.

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Table 1. Characteristics of all participants

Characteristic Male patients(N=28)

Female patients(N=25)

Male controls(N=21)

Female controls(N=21)

Mean SD Mean SD Mean SD Mean SD

Age (years) 26.3(19-45y)

6.7 28.7(19-41y)

6.4 26.9(20-40y)

5.0 26.4(20-34y)

4.4

Subjects’ education (1) 2.71 1.08 2.96 0.89 3.05 0.97 3.19 1.03

PANSS Positive Syndrome scale scores(2)

11.29 3.56 10.92 4.03

PANSS Negative syndrome scale scores(2)

15.11 4.75 13.56 5.06

PANSS General symptom scores(2)

24.64 4.13 26.64 7.63

Duration of illness (years) (2)

4.73 3.66 7.00 5.51

Age at first psychosis(2)

22.93 5.65 23.16 4.90

Number of hospitalizations(2)

1.71 1.33 2.04 1.57

Dose of atypical antipsychotics(2,3)

14.29 6.34 13.13 5.28

(1) Education was measured on a 4-point scale: low (1); middle (2); high (3); university (4)(2) Differences between male and female patients were non-significant(3) Dose of atypical antipsychotics in mg olanzapine equivalents (Dose conversion: 20

mg of olanzapine is equivalent to 6 mg of risperidone, 700 mg of quetiapine or 500 mg of clozapine; ref.: Kohler et al., 2003) Olanzapine (N=18; range = 10–25 mg; mean dose 15 mg) Clozapine (N=19; range = 75–750 mg; mean dose 350 mg = 14 mg equivalent olanzapine) Risperidone (N=10; range = 1–8 mg; mean dose 3.5 mg = 11 mg equivalent olanzapine) Quetiapine (N=6; range = 400–700 mg; mean dose 500 mg = 15 mg equivalent olanzapine)

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Fig.1. Example frames from two expression sequences (from left to right, 0 – 100% emotion), in face view.

2.3. Control taskThe Benton and Van Allen Test of Facial Recognition was administered to measure possible difficulties with general face processing (Benton et al., 1983).

2.4. ProcedureSubjects were presented with 3 practice trials, followed by the 48 randomly or-dered trials of the Facial Affect Recognition Task.

2.5. Statistical analysisAccuracy scores were analysed by a MANOVA (Group and Sex) for all emotions combined, side and face view, clustered in positive (happy, surprise) and nega-tive (anger, fear, sadness, disgust) emotions, and a post-hoc test for positive and negative emotions as separate categories. Sensitivity was calculated from trials on which the expression was correctly recognised. Sensitivity scores were ana-lysed in the same way as the accuracy scores.

3. Results3.1. Clinical variablesAs can be seen in Table 1, no differences were found between male and female patients in severity of negative symptoms, positive symptoms and general psy-chopathology sub-scale, measured by the PANSS.

The scores on the Benton Facial Recognition Test showed no significant dif-ferences between men and women (F (df 1,91) = 0.4; p = 0.55) nor between patients and controls (F (df 1,91) = 0.8; p = 0.39), indicating patients had no difficulties in recognising faces in general.

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3.2. Accuracy Accuracy was defined as the percentage of correct identifications for each ex-pression. The results of all subjects are listed in Table 2. The data were normally distributed. An overall MANOVA including the two categories of positive emotions and negative emotions (face + side view) revealed a main effect of Group (F(df 2,90) = 4.7; p = 0.012), with controls performing better than patients, and of Sex (F (df 2,90) = 8.1; p = 0.001), with women performing better than men, but no interaction between Group and Sex (F (df 2,90) = 1.0; p = 0.36). A post-hoc test showed that this effect was specific for negative emotions, with a main effect of Group (F (df 1,91) = 9.3; p = 0.003), and of Sex (F (df 1,91) = 16.3; p<0.0005), indicating that control subjects performed better than patients. The interaction between Group and Sex was again not significant (F (df 1,91) = 0.6; p = 0.43).

On positive emotions no significant main effects of Group (F (df 1,91) = 0.06; p = 0.81) or Sex (F (df 1,91) = 0.1; p = 0.72) were found. Because surprise is sometimes not regarded as a positive emotion (Ekman, 1982), we conduct-ed separate analyses for the emotions surprise and happy, which remained in-significant.

Since some emotions showed high error scores in control subjects (specifically men), we conducted an additional analysis, including only the data in which male controls reached scores of 70 -100% correct answers (anger, face + side view; happy, face + side view; disgust, face view; surprise, side view). This analysis showed a significant effect of Group (F (df 1,91) = 4.6; p = 0.035), and of Sex (F (df 1,91) = 10.4; p = 0.002) and a significant interaction between Group and Sex (F (df 1,91) = 10.4; p = 0.002), with female patients performing as well as female and male controls, and male patients performing significantly worse than the other three groups.

Table 2 shows the percentage correct responses for individual emotions.

Table 2. Percentage accuracy scores of positive and negative emotions

Characteristic Male patients (N=28)

Female patients(N=25)

Male controls (N=21)

Female controls (N=21)

Accuracy (side + face)

Mean SD Mean SD Mean SD Mean SD

Negative all 53.68 11.6 63.25 9.2 61.31 8.5 67.71 7.8

anger 75.89 16.3 95.50 7.1 86.31 9.6 89.29 10.7

disgust 54.46 20.2 54.00 13.8 63.69 18.5 67.26 20.7

fear 24.55 19.7 36.50 21.0 33.33 18.7 42.26 14.0

sadness 59.82 21.1 67.00 21.6 61.90 20.3 72.02 11.8

Positive all 80.13 9.5 83.25 10.2 83.04 6.9 81.25 8.2

happy 97.77 6.0 99.50 2.5 99.40 2.7 99.40 2.7

surprise 62.50 20.1 67.00 13.9 66.67 13.9 63.10 17.0

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34 Emotion recognition

3.3. Sensitivity Sensitivity was defined as the intensity at which the emotions were recognised. When only correct trials (in terms of accuracy) were taken into account, no ef-fects of Group or Sex were observed. However, since accuracy and sensitivi-ty were not correlated, we also conducted a sensitivity analysis on all trials. An overall MANOVA including the two categories of positive emotions and negative emotions showed a main effect of Group (F (df 2,90) = 3.0; p = 0.05), but not of Sex. A post-hoc test showed that this effect was specific for negative emotions, with a main effect of Group (F (df 1,91) = 6.1; p = 0.02), indicating that control subjects performed better than patients.

4. Discussion This study investigated whether women were more accurate at identifying facial emotions than men. Moreover, we examined if these sex differences were affect-ed by schizophrenia. Consistent with previous research in healthy subjects we observed a clear sex difference in the ability to recognise facial emotions, espe-cially negative ones, with women outperforming men. This female advantage was not affected by schizophrenia, even though patients as a group performed worse than controls. When the data analysis was limited to the tests where male con-trols reached correct scores of 70-100% , an interaction between Group and Sex was found, implying male patients performed the worst of all four groups.

Previous studies in healthy subjects have consistently indicated that wom-en are more accurate in processing negative facial emotions than men (McClure, 2000). Consistent with these findings, in this study women with schizophrenia performed better than men with schizophrenia. This may be due to a general ad-vantage in emotional skills in women as compared to men. Since impairment in emotion processing has been shown to contribute to social dysfunctioning (Mue-ser et al., 1996; Hooker & Park, 2002; Kee et al., 2003), the deficit in recognition of negative affect in male patients might explain, in part, why they are more im-paired in social life than women with this illness.

Although we found differences between men and women and between pa-tients and controls in accuracy scores, no differences were observed between these groups in sensitivity scores when only correctly identified emotions were taken into account. This is in contrast to a study by Kohler et al. (2003), who did find differences between schizophrenia patients and controls in accuracy scores as well as in sensitivity scores. This discrepancy may be explained by procedural differences between the studies. Whereas Kohler first required a sensitivity judge-ment, we first asked the subjects to identify the emotional expression at 100% intensity, and subsequently to make a sensitivity judgement. A limitation of our approach might have been that subjects already knew for which emotion to look, which may have influenced the sensitivity judgement.

Because female schizophrenia patients generally present with less severe (negative) symptoms than male patients (Leung & Chue, 2000), in the present study care was taken to avoid confounding effects of symptom severity. Indeed,

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we can be confident that the sex differences we found in the patients cannot be attributed to sex differences in severity of illness, because severity of symptoms and dosage of medication did not show significant differences between male and female patients. Duration of illness even tended to be longer in women than in men. Thus, the female patients in this study may be considered to be relatively ill, which lends additional credibility to our findings.

Although the exact neural underpinnings of sex differences in emotional face recognition remain unknown, one could speculate that specific sex differences in brain processing might contribute to this finding. Indeed, a number of studies have suggested that different neuronal systems might be involved in the processing of faces and facial affect in men compared to women. Specifically, these studies suggest that men rely more on right hemisphere processing of emotional stim-uli than women do. For example, data from ERP studies (Shucard et al., 1981; Shucard & Shucard, 1990) showed greater right hemisphere activation in men during emotion processing. Furthermore, in healthy prepubertal boys and girls, Everhart (2001) found different patterns in ERP amplitudes during a facial-af-fect-identification task: higher right hemisphere amplitude in boys, higher left hemisphere amplitude in girls. In an fMRI study (Lee et al., 2002) on facial af-fect recognition in healthy subjects, men and women showed different patterns of brain activation during the viewing of sad and happy faces. While happy faces initiated relatively more left hemisphere activation in both sexes, sad emotions elicited more left hemisphere activation in women and right hemisphere activa-tion in men. Results of other studies suggested a greater extent of lateralization in emotional perception in men than in women (Killgore, 2000; Killgore & Yurge-lun-Todd, 2001). In addition, studies on emotional memory (Cahill, 2003; Cahill et al., 2004) also showed gender-related lateralization of amygdala function, with more right lateralization in men and more left lateralization in women. Schizophre-nia has been associated with dysfunction of right hemisphere regions involved in emotion processing (Borod et al., 1993; Cutting, 1991, 1992; Kucharska-Pietura et al., 2002; Ross et al., 2001). If facial emotion processing indeed is more later-alized to the right hemisphere in men than in women, such a dysfunction would have stronger implications for male patients than for female patients, especially in processing negative emotions.

In conclusion, the superior performance in emotion perception tasks in wom-en as compared to men, is not affected by schizophrenia. This may explain in part why women with schizophrenia are less impaired in social life than men with schizophrenia. In addition, this may have implications for the understanding of social dysfunction in male patients. Therefore, it may be advisable to specifically tailor training programs to treat deficits in affect perception (Penn et al., 2000; Fromman et al., 2003) to the needs of male patients. Finally, the results of this study stress the importance of taking into account the influence of sex differenc-es on emotional processing in schizophrenia.

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5. ReferencesAleman A., Kahn R.S., Selten J-P., 2003. Sex differences in the risk of schizophrenia. Evidence from meta-analysis. Arch. Gen. Psychiatry 60, 565-571.

Andreasen N.C., Flaum M., Arndt S., 1992. The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Arch. Gen. Psychiatry 49, 615-623.

Benton A.L., Sivan A.B., Hamsher K. de S., Varney N.R., Spreen O., 1983. Benton’s Test of Facial Recognition, Oxford University Press, New York.

Borod J.C., Martin C.C., Alpert M., Brozgold A., Welkowitz J., 1993. Perception of facial emotion in schizophrenic and right brain-damaged patients. J. of Nervous and Mental Disease 181, 494-502.

Cahill L., 2003. Sex- and hemisphere-related influences on the neurobiology of emotionally influenced memory. Progress in Neuro-Psychopharmacology & Biological Psychiatry 27, 1235-1241.

Cahill L., Uncapher M., Kilpatrick L., Alkire M.K., Turner J., 2004. Sex-related hemispheric lateralization of amygdala function in emotionally influenced memory: An fMRI investigation. Learning & Memory 11, 261-266.

Castle D., Wessely S., Murray R.M., 1993. Sex and schizophrenia: effects of diagnostic stringency, and associations with premorbid variables. Br. J. Psychiatry 162, 658-664.

Castle D.J., Abel K., Takei N., Murray R.M., 1995. Gender differences in schizophrenia: hormonal effect or subtypes? Schizophr. Bull. 21, 1-12.

Cutting J., 1991. Delusional misidentification and the role of the right hemisphere in the appreciation of identity. Br. J. Psychiatry (Suppl) 14, 70-75.

Cutting J., 1992. The role of right hemisphere dysfunction in psychiatric disorders. Br. J. Psychiatry 160, 583-588.

Edwards J., Jackson H.J., Pattison P.E., 2002. Emotion recognition via facial expression and affective prosody in schizophrenia: a methodological review. Clin. Psychol. Rev. 22, 789-832. Erratum in: 2002, Clin. Psychol. Rev. 22, 1267-1285.

Ekman P., 1982. Emotion in the human face, Cambridge University Press, Cambridge.

Ekman P., 1999. Facial expressions, in: Dalgleish T. and Power T. (Eds.), The Handbook of Cognition and Emotion. John Wiley & Sons, Ltd., Sussex, U.K.: pp. 301-320.

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Everhart D.E., Shucard J.L., Quatrin T., Shucard D.W., 2001. Sex-related differences in event-related potentials, face recognition, and facial affect processing in prepubertal children. Neuropsychology 15, 329-341.

Frigerio E., Burt D.M., Montagne B., Murray L.K., Perrett D.I. 2002. Facial affect perception in alcoholics. Psychiatry Research 113, 161-171.

Fromman N., Streit M., Wölwer W., 2003. Remediation of facial affect recognition impairments in patients with schizophrenia: a new training program. Psychiatry Research 117, 281-284.

Goldstein J.M., Lewine R.R.J., 2000. Overview of sex differences in schizophrenia: where have we been and where do we go from here? In: Castle D.J., McGrath J.J., Kulkarni J. (Eds.), Women and schizophrenia.. Mass. Cambridge University Press, Cambridge, pp 111-153.

Gosselin P., Kirouac G., Doré F.Y., 1995. Components and recognition of facial expression in the communication of emotion by actors. Journal of Personality and Social Psychology 68, 83-96.

Häfner H., Maurer K., Löffler W., Fätkenheuer B., Heiden an der W., Riecher-Rössler A., Behrens S., Gattaz W., 1994. The epidemiology of early schizophrenia. Influence of age and gender on onset and early course. Br. J. Psychiatry 164, (Suppl 23) 29-38.

Häfner H., Maurer K., Loffler W., an der Heiden W., Munk-Jorgensen P., Hambrecht M., Riecher-Rossler A. The ABC Schizophrenia Study: a preliminary overview of the results. Soc Psychiatry Psychiatr Epidemiol. 1998 Aug;33(8):380-6.

Hall J.A., 1978. Gender effects in decoding non-verbal cues. Psychological Bulletin 85, 845-857.

Hall J.A., 1984. Non-verbal sex differences: Communication Accuracy and expressive style. Baltimore: John Hopkins University Press.

Hooker C., Park S., 2002. Emotion processing and its relationship to social functioning in schizophrenia patients. Psychiatry Research 112, 41-50.

Kay S.R., Opler L.A., Fiszbein A., 1986. Positive and Negative Syndrome Scale (PANSS). MultiHealth Systems Inc. North Tonawanda, NY.

Kee K.S., Green M.F., Mintz J., Brekke J.S., 2003. Is emotion processing a predictor of functional outcome in schizophrenia? Schizophr. Bull. 29, 487-497.

Page 38: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

38 Emotion recognition

Killgore W.D.S., 2000. Sex differences in identifying the facial affect of normal and mirror-reversed faces. Percept. Mot. Skills 91, 525-530.

Killgore W.D.S., Yurgelun-Todd D.A., 2001. Sex differences in amygdala activation during the perception of facial affect. NeuroReport 12, 2543-2547.

Kirita T., Endo M., 1995. Happy face advantage in recognizing facial expressions. Acta Psychol. 89, 149-163.

Kohler C.G., Turner T.H., Bilker W.B., Brensinger C.M., Siegel S.J., Kanes S.J., Gur R.E., Gur R.C., 2003. Facial emotion recognition in schizophrenia: intensity effects and error pattern. Am. J. Psychiatry 160, 1768-1774.

Kucharska-Pietura K., David A.S., Dropko P., Klimkowski M., 2002. The perception of emotional chimeric faces in schizophrenia: further evidence of right hemisphere dysfunction. Neuropsychiatry Neuropsychol. Behav. Neurol. 15, 72-78.

Lee T.M.C., Liu H., Hoosain R., Liao W., Wu C., Yuen K.S.L., Chan C.C.H., Fox P.T., GAO J., 2002. Gender differences in neural correlates of recognition of happy and sad faces in humans assessed by functional magnetic resonance imaging. Neuroscience Letters 333, 13-16.

Leung A., Chue P., 2000. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr. Scand. (Suppl.) 101, 3-38.

Mandal M.K., Pandey R., Prasad A.B., 1998. Facial expressions of emotions and schizophrenia: a review. Schizophr. Bull. 24, 399-412.

McClure E.B., 2000. A meta-analytic review of sex differences in facial expression processing and their development in infants, children, and adolescents. Psychol. Bull. 126, 424-453.

Miura M., 1993. Individual differences in the perception of facial expression: the relation to sex difference and cognitive mode. Shinrigaku Kenkyu 63, 409-413.

Montagne B., Kessels R.P.C., Frigerio E., De Haan E.H.F., Perrett D.I. 2005. Sex differences in the perception ofaffective facial expressions: Do men really lack emotional sensitivity? Cognitive Processing (in press).

Mueser K., Doonan R., Penn D., Blanchard J., Bellack A., Nishith P., DeLeon J., 1996. Emotion recognition and social competence in chronic schizophrenia. J. of Abnormal Psychology 105, 271-275.

Penn D., Spaulding W., Reed D., Sullivan M., 1996. The relationship of social cognition to ward behaviour in chronic schizophrenia. Schizophrenia Research 20, 327-335.

Page 39: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

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Penn D., Combs D.R., Ritchie M., Francis J., Cassisi J., Morris S., Townend M., 2000. Emotion recognition in schizophrenia: further investigation of generalized versus specific deficits models. J. Abnorm. Psychol. 109, 512-516.

Poole J.H., Tobias F., Vinogradow S., 2000. The functional relevance of affect recognition errors in schizophrenia. Journal of the International Neuropsychological Society 6, 649-658.

Ross E.D., Orbelo D.M., Cartwright J., Hansel S., Burgard M., Testa J.A., Buck R., 2001. Affective-prosodic deficits in schizophrenia: comparison to patients with brain damage and relation to schizophrenic symptoms [corrected]. J. Neurol. Neurosurg. Psychiatry. 70, 597-604. Erratum in: 2001, J. Neurol. Neurosurg. Psychiatry 71, 283.

Rowland D. & Perrett D., 1995. Manipulating facial appearance through shape and colour. IEEE Computer Graphics and Applications.15, 70-76.

Seeman M. & Lang M., 1990. The role of estrogens in schizophrenia gender differences. Schizophr. Bull.16, 185-195.

Sheehan D.V., Lecrubier Y., Sheehan K.H., Amorim P., Janavs J., Weiller E., Hergueta T., Baker R., Dunbar G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59, 22-33.

Shucard J.L., Shucard D.W., Cummins K.R., Campos J.J., 1981. Auditory evoked potentials and sex-related differences in brain development. Brain and Language 13, 91-102.

Shucard J.L., Shucard D.W., 1990. Auditory evoked potentials and hand preference in 6-month-old infants: Possible gender-related difference in cerebral organisation. Developmental Psychology 26, 923-930.

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Part 2

The processing of emotional prosody and semantics in schizophrenia: relationship to

gender and IQ.

Marion R.M. ScholtenAndré AlemanRené S. Kahn

Manuscript in revision

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42 Emotion recognition

AbstractBackground: This study examined whether normal sex differences in emotional language processing and visuo-spatial processing are preserved in schizophrenia. In addition, the relationship between these variables and IQ scores was studied.Method: 48 patients with schizophrenia (25m, 23 f) and 46 controls (23 m, 23 f) were assessed using an emotional language task, in which women generally outperform men, and a spatial mental rotation task, in which men typically ex-cel. The language task targeted emotional semantics and prosody and consist-ed of 96 sentences in 4 conditions: (1) neutral content, spoken in a happy, sad, angry or anxious tone; (2) neutral tone with emotional content; (3) emotional tone with incongruous emotional content; (4) emotional content with incongru-ous emotional tone. In condition 3, participants were required to ignore the emo-tional content and in condition 4, the emotional prosody. Results: Patients were significantly impaired on all conditions of the emotional language task. Women outperformed men across groups on the first three condi-tions. Controlling for IQ revealed no significant effect on the group- and sex dif-ferences in prosodic scores, but reduced the differences on emotional semantics to an insignificant trend. On the rotation task, as expected, the healthy men out-performed the healthy women. However, male patients, female patients and fe-male controls all obtained similar scores. Conclusions: The female advantage in emotional prosodic processing is pre-served in schizophrenia, whereas the male advantage in visuo-spatial processing is lost. Controlling for IQ was found to modify the group- and sex differences in processing emotional semantics, but not in processing emotional prosody. Pres-ervation of a female advantage in emotional prosodic processing may explain, in part, why social functioning is less compromised in women with schizophre-nia than in men.

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Chapter two 43

1. IntroductionThe risk of developing schizophrenia is not only lower for women compared to men (Aleman et al. 2003), but women with schizophrenia have also been doc-umented to show a less severe course of illness, with better preservation of so-cial skills, than men (Goldstein et al., 2000; Leung & Chue, 2000). Differences between men and women in the pace of brain development (slower in men) and in asymmetry in brain structures (more lateralisation in men), as regulated by prenatal effects of sex steroid hormones, have been suggested to underlie these differences in the manifestation of the illness (Collaer & Hines, 1995; Diamond, 1989; Geschwind & Galaburda, 1987). In healthy subjects, sexual dimorphism of the brain has been related to differences in performance on cognitive and emo-tional tasks between the sexes. Widely reported domains of sexual dimorphic performance are verbal processing (Halpern & LaMay, 2000; Kimura, 1999) and emotion recognition (Hall, 1978, 1984; McClure, 2000), both vital for social func-tioning and better in women, and visuo-spatial processing, better in men (Linn & Petersen, 1985; Roberts & Bell, 2003).

In research on schizophrenia, several studies have shown patients to be im-paired in semantic processing (Condray et al., 2002; Nestor et al., 2001; Wal-der et al., 2006), in the recognition of emotional speech (Edwards et al., 2001; Leentjens et al, 1998; Murphy & Cutting, 1990; Ross et al., 2001), and non-verbal emotional cues (Edwards et al., 2002; Kohler et al., 2003; Mandal et al., 1998). These difficulties were found to be associated with impoverished social skills (Hooker & Park, 2002; Mueser et al., 1996; Penn et al., 1996; Poole et al., 2000). Since male patients are more impaired in social functioning than female patients, this might in part be the result of the preservation of the female advan-tage in verbal and emotional processing relative to men.

Our main hypothesis was that sex differences in cognitive and emotional processing are preserved in schizophrenia. Indeed, in a previous study (Scholten et al, 2005) we found preservation of the female advantage in facial affect rec-ognition. Since social interaction also strongly depends on the recognition of emotional speech and because verbal emotion processing has been found to be compromised in schizophrenia, we chose in this study to focus on the effect of schizophrenia on sex differences in emotion recognition of spoken language. In order to understand the emotional relevance of a spoken message, attention has to be paid not only to the semantic meaning of the message, but to the affec-tive prosody, or ‘tone of voice’ as well. Both types of information are processed simultaneously (Buchanan et al., 2000; Gandour et al., 2004; Schirmer et al., 2002; Tong et al., 2005), and may be incongruent in affective meaning, as in the case of irony, sarcasm, or indeed by just not saying what is meant. Therefore, we were particularly interested in the recognition of the incongruous conditions (incongruence in emotional content and affective prosody), because the ability to understand or inhibit (emotional) conflicting information is crucial for success-ful communication (Carton et al., 1999; Trauner et al., 1996). Since general in-tellectual deficits have been hypothesised to underlie deficits in affect recognition in schizophrenia (Edwards, 2001; Poole, 1999), IQ measures were also obtained.

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44 Emotion recognition

In addition we examined whether the male advantage in visuo-spatial ability is preserved in schizophrenic subjects.

In patients with schizophrenia, we expected a female advantage to be pre-served on tasks that depend on both language and emotion processing, and a male advantage to be preserved in visuo-spatial processing. Higher scores on both tasks were expected to correlate with higher IQ scores.

2. Method2.1. Participants Forty-eight patients with schizophrenia (25 m, 23 f) and 46 healthy controls (23 m, 23 f), all native Dutch speakers, participated in this study.

All patients attended the out-patient clinic of the Schizophrenia Research Unit at the Utrecht University Hospital. The psychiatric diagnosis had been confirmed by an independent psychiatrist via a structured diagnostic interview (the Compre-hensive Assessment of Symptoms and History (CASH); Andreasen et al., 1992). All patients satisfied the DSM-IV-R criteria for schizophrenia. To avoid any effects of affective symptoms and co-medication on the scores, only patients without prom-inent affective symptoms (e.g. no schizo-affective disorder, no concurrent depres-sion) and no other concomitant axis I disorder were recruited for the study. Most female (n= 22) and male (n=21) patients were diagnosed with the paranoid sub-type of schizophrenia. Only 1 female patient and 2 male patients were diagnosed with a disorganised subtype, and 2 male patients with a residual subtype.

At the time of testing, all patients were taking atypical antipsychotics without any co-medication, such as tranquillisers or antidepressants. Patients were stud-ied while clinically stable (at least 6 weeks stable on the same dosage of antipsy-chotics). Positive and negative symptoms, including their severity, were measured with a structured interview (the Positive And Negative Syndrome Scale (PANSS); Kay et al., 1986), on the day of testing. Male and female patients did not differ significantly in age at onset of the first psychosis, the number of hospitalisations, the duration of illness, or the dosage of their medication.

The control subjects were either volunteers from the Utrecht University Hos-pital or had been recruited through advertisements in local newspapers. They had been screened, using the Mini-International Neuropsychiatric Interview Plus (MINI-Plus), for current or past psychiatric illness, in themselves and their first-degree relatives (Sheehan et al., 1998).

All participants were assessed with the Dutch version (Schmand et al., 1992) of the National Adult Reading Test (NART; Nelson, 1982), a test devised to pre-dict premorbid intellectual functioning in subjects suspected of cognitive decline. Scores on the Raven Standard progressive matrices (Raven et al., 1996) were used as an index for non-verbal, performal IQ.

All subjects were screened using a medical history questionnaire and inter-view. Exclusion criteria included a history of neurological or systemic disease, any hearing impairment, and diagnosis of an active substance use disorder in the 3 months prior to study.

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Chapter two 45

In order to avoid any effects of the menstrual cycle, all female participants were tested in the first 10 days of their cycle (starting from day 1 of menstru-ation). Patients and control subjects did not differ significantly in terms of ed-ucation, premorbid estimated IQ (NART), or age within sex, but differed in age between groups and in non-verbal IQ (Raven).

Group characteristics of patients and controls are reported in Table 1.

After receiving a complete description of the study, written informed consent was obtained from the subjects. The study had been approved by the Medical Ethics Committee of the University Medical Center Utrecht.

2.2. Procedure2.2.1. Emotional language Task An emotional language task was developed using stimuli derived from Vinger-hoets et al., (2003). The stimulus material consisted of 96 sentences across 4 conditions. In condition 1 (affective prosody-neutral content), 24 sentences with a neutral semantic content, spoken in a happy, sad, angry or anxious tone were presented and the participants were instructed to identify the emotion from the tone of voice. For example: ‘Silicones protect the surface’ spoken in a sad tone. In condition 2 (emotional content-neutral prosody), 24 sentences with a neutral tone and an emotional semantic content (happy, sad, angry or anxious) were pre-sented and the participants had to determine the emotion that was reflected in the content. For example: ‘No one looks after her sister’ (sad content). Condition 3 (affective prosody-incongruous emotional content) and 4 (emotional content-incongruous affective prosody) consisted each of 24 sentences with emotional semantic content and an incongruous affective tone. In condition 3 participants were required to attend to the affective prosody of the sentence, while ignoring the incongruous emotional content, whereas in condition 4 they had to attend to the emotional content of the sentence, while ignoring the incongruous affective prosody. For example: ‘The man bought a nice present for his wife’, spoken in an angry tone. When attending to the emotional content, the correct answer would be ‘happy’; attending to the affective prosody the correct answer would be ‘an-gry’. In order to control for sex differences in the affective prosody of the spoken sentences, in all conditions 12 of the sentences were articulated by a profession-al male actor and 12 by a female actor. In each condition, the 4 types of emo-tions (happy, sad, angry, anxious) were equally divided over 24 sentences in a pseudo-random order. All stimuli were presented binaurally through earphones, with a 2-seconds inter stimulus interval between each sentence, while the Dutch words for the 4 emotions were displayed on a computer screen. The testing of each condition was preceded by a series of 4 practice trials. Participants were in-structed to name the perceived emotion, and their answers were written down by a test-assistant.

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46 Emotion recognition

Table 1. Characteristics of all participants

Characteristic Male patients(N=25*/26)

Female Patients(N=23*/24)

Male controls(N=23*/24)

Female controls(N=23*/24)

Mean

Prosody task*/Rotation task

SD Mean

Prosody task*/Rotation task

SD Mean

Prosody task*/Rotation task

SD Mean

Prosody task*/Rotation task

SD

Age (years) 29.5/29.6(19-40 y)

7.0/6.9

32.2/31.9(20-39 y)

6.6/6.6

26.6/27.1(19-41 y)

6.2/5.9

29.0/28.3(20-39 y)

6.2/6.2

Subjects’ education (1)

2.1/2.1

1.0/1.0

2.5/2.5

1.0/.9

2.4/2.5

.8/

.82.4/2.4

.8/.8

NLV-IQ 107.2/107.1

9.6/9.4

110.2/109.3

8.3/10.1

108.7/109.5

6.1/4.8

107.8/107.1

6.5/7.4

Raven 8.4/8.3

2.4/2.4

9.0/8.8

2.0/2.2

9.6/9.8

2.0/1.9

9.8/9.9

1.8/1.8

PANSS Positive scores(2)

11.6/11.6

4.5/4.5

9.9/9.9

3.2/3.1

PANSS Negative scores(2)

16.4/16.2

6.6/6.6

13.6/13.9

5.0/5.2

PANSS General scores(2)

26.8/26.8

9.1/8.9

24.6/24.6

5.4/5.2

Duration ofillness (years)(2)

7.0/7.1

4.9/4.8

8.5/8.2

6.6/6.6

Age at first psychosis(2)

22.6/22.5

5.4/5.3

23.7/23.7

5.7/5.6

Number of hospitalisations(2)

1.5/1.5

1.2/1.2

1.3/1.3

1.3/1.2

Dose of atypical antipsychotics(2,3)

11.9/12.4

4.7/5.3

10.4/10.1

5.1/5.2

* Not all subjects participated in both tasks(1) Education was measured on a 4-point scale: low (1); middle (2); high (3); university (4)(2) Differences between male and female patients were non-significant(3) Dose of atypical antipsychotics in mg olanzapine equivalents (Dose conversion: 20

mg of olanzapine is equivalent to 6 mg of risperidone, 700 mg of quetiapine, 15 mg aripiprazole or 500 mg of clozapine; ref.: Kohler et al., 2003); Olanzapine (N=21; range = 5-20 mg; mean dose 10 mg; Clozapine (N= 11; range = 100-650 mg; mean dose 336 mg = 13.5 mg equivalent olanzapine); Risperidone (N= 10; range = 1.5-6 mg; mean dose 3.5 mg = 12 mg equivalent olanzapine); Quetiapine (N=1; dose 400 mg = 16 mg equivalent olanzapine); Aripiprazole (N=7; range = 15 mg; mean dose 15 mg = 15 mg equivalent olanzapine)

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2.2.2. Mental Rotation TaskA computerised version of the Mental Rotation Task, consisting of 20 pairs of three-dimensional geometric line drawings, was presented to all participants (Shepard & Metzler, 1971). Subjects were asked to compare the mental representations of two line drawing objects, presented at different orientations, and to indicate, by pressing a left or right button, whether these figures were identical or differ-ent. Subjects were instructed to work as fast as possible, but not at the cost of accuracy. Subject’s Error Rate (ER) and mean Response Time (RT) were record-ed by the computer.

2.3. Statistical analysisThe accuracy scores derived from the Rotation task and from each of the 4 con-ditions of the emotional language task (affective prosody-neutral content (1); emotional content-neutral prosody (2); affective prosody-incongruous emotion-al content (3); emotional content-incongruous affective prosody (4)), were ana-lysed by an ANOVA (Group and Sex). In addition, analyses of co-variance were conducted with age and IQ measures (scores on NART and Raven) as covariates. In order to explore within- subjects effects between (i) condition 1 and 3 and (ii) between condition 2 and 4, repeated measures analyses were conducted.

An extra analysis was computed for the effect of each individual emotion (hap-py, anger, fear and sad) on all conditions combined, and error patterns were an-alysed for the incongruous conditions.

Pearson correlation coefficients were computed for associations between pro-sodic/semantic and spatial data and 1) IQ measures and 2) patient variables (du-ration of illness, dosage of medication, PANSS-scores).

3. Results3.1. Clinical variablesAs can be seen in Table 1, no significant differences were found between male and female patients in the severity of negative symptoms, positive symptoms or general psychopathology as measured by the PANSS.

3.2. Accuracy scores emotional language taskAccuracy was defined as the proportion of correctly identified expressions. The results for all subjects are listed in Table 2.

A main effect of Group (patients versus controls) was found for affective prosody-neutral content (condition 1) (F(df 1,90) = 22.7; p < .001), emotional content-neutral prosody (condition 2) (F(df 1,90) = 5.5; p = .021), affective pros-ody-incongruous emotional content (condition 3) (F(df 1,90) = 6.4; p = .013), and emotional content-incongruous affective prosody (condition 4) (F(df 1,90) = 15.1; p <.001), with controls performing better than patients. A main effect of Sex was found for condition 1 (F(df 1,90) = 8.5; p = .005), condition 2 (F(df 1,90) = 4.6; p = .035), and condition 3 (F(df 1,90) = 5.8; p = .018), with women per-

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48 Emotion recognition

forming better than men. Condition 4 did not show an effect of Sex. No interac-tions were found between Group and Sex for any of the conditions.

An ANCOVA on each condition, with age or NART as covariates, revealed no effect of age on performance and no effect of NART on group- or sex differences. However, a separate ANCOVA on each condition with the Raven (non-verbal IQ) as a covariate, showed a significant effect of IQ on task performance in all condi-tions. An effect of Group was not longer significant on emotional semantics-neutral content (condition 2) (F(df 1,89) = 2.9; p = .092), and emotional prosody-incon-gruous emotional content (condition 3) (F(df 1,89) = 3.2; p = .078); on emotion-al semantics-neutral content (condition 2) an effect of Sex only showed a trend (F(df 1,89) = 3.6; p = .061), after correction for IQ. Effects of Group and Sex were not influenced by IQ in condition 1 (emotional prosody-neutral content) and 4 (emotional content-incongruous affective prosody).

Repeated measures analyses between condition 1 and 3 (affective prosody with and without distraction of emotional semantics) and between condition 2 and 4 (emotional semantics with and without distraction of affective prosody) did not reveal any within-subjects effects. No correlations were found between scores on the emotional language task and duration of illness or dosage of medication. Low-er affective prosody scores (condition 1) correlated with higher negative symp-tom scores (r = -.318; p= .028). Higher affective prosody scores correlated with higher age of first psychosis (r =.357; p = .013). Higher number of hospitalisa-tions correlated with lower scores on condition 3 (r = -.303; p = .036) and con-dition 4 (r = -.366; p = .011). Higher scores on the Raven correlated with higher scores on all conditions: condition 1 (r =.326; p = .001), condition 2 (r =.344; p = .001), condition 3 (r =.405; p < .001), and condition 4 (r =.517; p < .001); higher scores on the NART only correlated positively with scores on condition 4 (r =.338; p = .001).

The emotions fear, and to a lesser extent sadness, were found to be poorly recognised by all groups in all conditions (85 % correct) compared to the emo-tions anger and happiness (95 % correct).

Analysis of the errors made in the recognition of affective prosody with dis-traction of emotional incongruous content (condition 3), revealed that male pa-tients had often (54.4% of the errors) chosen an answer that applied to the ‘to be ignored’ emotional content. For the other groups the proportions making this error were 39% for female patients, 28.8 % for male controls and 18.5 % for fe-male controls.

3.3. Accuracy scores rotation taskAn ANCOVA with IQ (Raven) as a covariate, revealed an effect of IQ (F(df 1,93) = 26.2; p < .001), a main effect of Sex (F(df 1,93) = 9.1; p = .003), and a Sex x Group interaction (F(df 1,93) = 4.5; p = .036). Importantly, the effect of sex was limited to the male and female controls (F(df 1,46) = 8.8; p = .005). No sex difference was found between the male and female patients (F(df 1,48) = .02; p = .901). Age and NART as covariates revealed no significant effects.

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Chapter two 49

A positive correlation was found between scores on the rotation task and IQ measures (Raven (r =.451; p < .001), but not between spatial data and patient characteristics.Table 2 shows the proportions of correct responses for emotional language and spatial ability.

Table 2. Accuracy scores emotional language task and mental rotation task

Characteristic Male patients (N=25)

Female patients(N=23)

Male controls (N=23)

Female controls (N=23)

Emotional language task

Mean SD Mean SD Mean SD Mean SD

Affective prosody- neutral content (condition 1)

19.2 (80.0%)

2.4 21.0(87.5%)

1.9 21.7(90.4%)

1.7 22.2(92.5%)

1.4

Emotional content- neutral prosody (condition 2)

21.1(87.9%)

3.6 22.5(93.8%)

1.3 22.6(94.2%)

1.4 23.0(95.8%)

.8

Affective prosody-incongruous emotional content (condition 3)

18.4(76.7%)

4.7 20.4(85.0%)

3.2 20.5(85.4%)

2.2 21.7(90.4%)

1.7

Emotional content-incongruous affective prosody (condition 4)

22.0(91.7%)

2.4 22.7(94.6%)

1.6 23.6(98.3%)

.8 23.5(97.9%)

.7

Male patients (N=26)

Female patients(N=24)

Male controls (N=24)

Female controls (N=24)

Rotation task Mean SD Mean SD Mean SD Mean SD

Accuracy scores 13.5(67.5%)

3.8 13.4(67.0%)

3.2 16.1(80.5%)

2.3 12.8(64.0%)

5.0

Reaction time 7714 4318 7787 4958 6592 2057 7417 4822

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50 Emotion recognition

4. Discussion The aim of this study was to investigate whether the female advantage in emo-tional prosodic and semantic processing and the male advantage in visuo-spatial ability are preserved in schizophrenia, and to examine whether the scores ob-tained in both domains are related to IQ and to symptomatology.

Concerning emotional language processing, we found that healthy controls outperformed patients, and women outperformed men on affective prosody-neu-tral content (condition 1) and emotional content-neutral prosody (condition 2). However, with correction for IQ (Raven), only patient and sex differences in the scores on prosody (condition 1) reached significance, while differences on emo-tional semantics (condition 2) were reduced to an insignificant trend. This might imply that differences in the recognition of prosody between men and women and between patients and controls are relatively independent of general cogni-tive impairment. Deficits in prosodic processing were found to correlate signifi-cantly with severity of negative symptoms. This is in line with previous studies (Fricchione et al., 1986; Leitman et al., 2005) and is consistent with a recent model proposed by Aleman & Kahn (2005), in which emotion processing defi-cits are suggested to be central to schizophrenia and to form part of the nega-tive symptom dimension.

On the incongruous conditions of the emotional language task (incongruence between emotional tone and emotional content) women outperformed men on af-fective prosody-incongruent emotional content (condition 3), also after correction for IQ (Raven). All subjects made more errors in identifying emotional prosody with interference of incongruous emotional content (condition 3) than with neu-tral content (condition 1), but this difference between both tasks was not signif-icant. Furthermore, in line with a study by Besson et al. (2002), all participants showed more difficulty in ignoring semantics, while listening to prosody (condi-tion 3), than in ignoring prosody while listening to semantics (condition 4). This may in part be due to a ceiling effect on condition 4, with scores over 90% in all participants, although controls performed significantly better than patients. Analysis of the error patterns in identifying emotional prosody with distraction of emotional content (condition 3) revealed that, of all four groups, male patients most often chose an answer that applied to the ‘to be ignored’ emotional con-tent. Taken together, these results suggest that identifying the emotional content of a sentence is less difficult than recognising the affective prosody, and that the impact of the emotional content of a message on the interpretation of affective prosody is stronger in patients with schizophrenia, especially males, relative to controls. In confirmation of a previous study by Edwards et al. (2001), we also found that fearful and sad vocal expressions were the most difficult to recognise for all participants.

Although the mechanisms that underlie the sex differences in recognition of emotional language are not known, one could speculate that specific sex differ-ences in patterns of brain activation during speech processing may account for these findings. Results from several studies on language processing in healthy subjects suggest a greater extent of lateralisation in men than in women (Baxter

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et al., 2003; Rossell et al., 2002; Shaywitz et al., 1995). A study by Schirmer et al. (2004) reported that processing of affective prosody initiates relatively more right hemisphere activation in both sexes, while processing emotional word va-lence elicits more bilateral activation in women and left hemisphere activation in men. In the case of schizophrenia, evidence from several fMRI studies suggests some abnormal reversal of lateralisation in speech processing, with relatively more left lateralisation in response to prosody (Mitchell et al., 2004) and relatively more right lateralisation in response to semantics (Woodruff et al., 1997). Since men and women differ in their basic patterns of brain activation in speech processing, changes in lateralisation may impact differently on both sexes.

In contrast to the findings of our own study, a study by Bozikas et al. (2006) reported only male patients with schizophrenia to be impaired in prosody per-ception, while female patients showed deficits in just recognising sadness. This discrepancy may be explained by differences in patient variables between male and female patients (or by the small number of women included in the Bozikas study, which limits statistical power). Notably, in our sample, male and female patients did not differ in age at first psychosis, although age at onset is usual-ly higher in women compared to men (Häfner et al., 1994, 2003). Since lower prosody scores were found to correlate with younger age of first psychosis this might explain why in our sample deficits in prosodic perception were shown in both male and female patients.

On the task of visuo-spatial ability, we replicated the previous findings of a male advantage on the mental rotation task in healthy participants (Burton et al., 2005; Linn & Peterson, 1985; Roberts & Bell, 2003), despite the fact that all women had been tested during menstruation, when oestrogen is low and spatial performance is best (Driscoll et al., 2005; Epting & Overman, 1998; Maki et al., 2002; Moody, 1997; Silverman & Phillips, 1993). However, differences in performance between male and female patients were not significant in our study. Remarkably, female patients and female controls obtained similar scores, whereas male patients per-formed considerably worse than male controls. Low oestrogen levels, reported in women with schizophrenia, irrespective of antipsychotic induced hyerprolactine-mia (Bergemann et al., 2005), may have facilitated visuo-spatial performance in the female patients. Furthermore, there is evidence that men and women differ in cerebral activation patterns during mental rotation (Jordan et al., 2002; Weiss et al., 2003), with right hemispheric advantage in men, but not in women (Rilea et al., 2004). A study by Siegel-Hinson & McKeever (2002) suggests that mental rotation ability is positively related to the magnitude of right hemispheric special-isation. Since schizophrenia has been associated with right hemisphere dysfunc-tion (Borod et al., 1993; Cutting, 1992; Kucharska-Pietura et al., 2002; Ross et al., 2001), this will have stronger implications for spatial ability in (right lateral-ised) male patients than in female patients.

Our findings on the mental rotation task are in contrast with a study by Ha-lari et al. (2006), which demonstrated that sexual dimorphism on a spatial task (favouring men), remains intact in patients with schizophrenia. This discrepan-

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cy may be explained by sample differences between the studies. Compared to the study by Halari, the duration of illness was shorter (8.5 versus 21.5 years) in the female patients of our study, which may have advanced preservation of their cognitive skills. Furthermore, the patients in Halari’s study were all treated with typical antipsychotics, while in our study all patients were on atypical antip-sychotic medication. Improvement on verbal tasks (Buchanan et al., 1994; Mull-er et al., 2005) and on spatial tasks (Gur et al., 2003; Harvey et al., 2003) has been linked to treatment with atypical antipsychotic medication, but not typical antipsychotics. Moreover, female patients have been reported to show a better treatment response to antipsychotics relative to male patients (Goldstein et al., 2002). These factors might explain why we found preservation of sexual dimor-phism on the verbal task in female patients, and loss of sexual dimorphism on the spatial task in male patients with schizophrenia.

A noteworthy strength of this study is the care that was taken to avoid con-founding effects of symptom severity, because female patients generally present at a later age of onset and with less severe (negative) symptoms than male pa-tients. Indeed, we are confident that the sex differences that were found, cannot be attributed to sex differences in the severity of illness, because age of onset, severity of symptoms and dosage of medication did not show significant differ-ences between the male and female patients. This lends additional credibility to our findings. A limitation of this study might be that the sample was a selective one, consisting of stabilised outpatients on atypical antipsychotics, without co-medication, recent drug abuse or comorbid affective symptoms.

In conclusion, women’s superior ability relative to men in identifying the af-fective prosody of a spoken message, with and without distraction of emotional content, is preserved in schizophrenia, albeit at a lower accuracy level compared to controls. However, the ability to recognise the emotional content of a mes-sage is highly influenced by IQ and does not show significant differences between men and women nor between patients and controls. Since the ability to recog-nise emotions in speech is essential for social interaction, the more severe defi-cits in recognition of affective prosody in male patients may explain, in part, the poorer social skills and global outcome in men compared to women with this ill-ness. In contrast, the male advantage in visuo-spatial processing was found to be compromised in schizophrenia. These data suggest that men and women em-ploy different cognitive strategies in verbal and spatial tasks, which may be based on sexual dimorphism in brain function. This could imply that the same neuro-cognitive defects might have different consequences in men and women. Since there is some evidence that the training of verbal-semantic encoding in patients with schizophrenia may improve the ability to identify social cues (Corrigan et al., 1995), especially male patients might benefit from this type of therapy. Finally, the results of this study stress the importance of taking into account the influ-ence of sex differences on emotional processing in schizophrenia.

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AcknowledgementsWe thank Professor G. Vingerhoets for providing the stimuli of the emotional language task.

A. Aleman was supported by a VernieuwingsImpuls grant (no 016.026.027) from the Netherlands Organisation for Scientific Research (NWO).

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5. ReferencesAleman, A., Kahn, R.S. & Selten, J-P. (2003). Sex differences in the risk of schizophrenia. Evidence from meta-analysis. Archives of General Psychiatry 60, 565-571.

Aleman, A., & Kahn, R.S. (2005). Strange feelings: do amygdala abnormalities dysregulate the emotional brain in schizophrenia? Progress in Neurobiology 77(5), 283-298.

Andreasen, N.C., Flaum, M. & Arndt, S. (1992). The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Archives of General Psychiatry 49, 615-623.

Baxter, L.C., Saykin, A.J., Flashman, L.A., Johnson, S.C., Guerin, S.J., Babcock, D.R. & Wishart, H.A. (2003). Sex differences in semantic language processing: a functional MRI study. Brain and Language 84(2), 264-272.

Bergemann, N., Mundt, C., Parzer, P., Jannakos, I., Nagl, I., Salbach, B., Klinga, K., Runnebaum, B. & Resch, F. (2005). Plasma concentrations of estradiol in women suffering from schizophrenia treated with conventional versus atypical antipsychotics. Schizophrenia Research 73(2-3), 357-366.

Besson, M., Magne, C. & Schon, D. (2002). Emotional prosody: sex differences in sensitivity to speech melody. Trends in Cognitive Science 6(10), 405-407.

Borod, J.C., Martin, C.C., Alpert, M., Brozgold, A. & Welkowitz, J. (1993). Perception of facial emotion in schizophrenic and right brain-damaged patients. Journal of Nervous and Mental Disease 181, 494-502.

Bozikas, V.P., Kosmidis, M.H., Anezoulaki, D., Giannakou, M., Andreou, C. & Karavatos, A. (2006). Impaired perception of affective prosody in schizophrenia. Journal of Neuropsychiatry and Clinical Neurosciences 18(1), 81-85.

Buchanan, R.W., Holstein, C. & Breier A. (1994). The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance. Biological Psychiatry 36(11), 717-725.

Buchanan, T.W., Lutz, K., Mirzazade, S., Specht, K., Shah, N.J., Zilles, K. & Jancke, L. (2000). Recognition of emotional prosody and verbal components of spoken language: an fMRI study. Brain Research. Cognitive Brain Research 9(3), 227-238.

Burton, L.A., Henninger, D. & Hafetz J. (2005). Gender differences in relations of mental rotation, verbal fluency, and SAT scores to finger length ratios as hormonal indexes. Developmental Neuropsychology 1, 493-505.

Page 55: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter two 55

Carton, J., Kessler, E. & Pape, C. 1999. Nonverbal decoding skills and relationship well-being in adults. Journal of Nonverbal Behaviour 23, 91-100.

Collaer, M.L. & Hines, M. (1995). Human behavioral sex differences: a role for gonadal hormones during early development? Psychological Bulletin 118(1), 55-107.

Condray, R., Steinhauer, S.R., van Kammen, D.P. & Kasparek A. (2002). The language system in schizophrenia: effects of capacity and linguistic structure. Schizophrenia Bulletin 28(3), 475-490.

Corrigan, P.W., Hirschbeck, J.N. & Wolfe, M. (1995). Memory and vigilance training to improve social perception in schizophrenia. Schizophrenia Research 17(3), 257-265.

Cutting, J. (1992). The role of right hemisphere dysfunction in psychiatric disorders. British Journal of Psychiatry 160, 583-588.

Diamond, M.C. (1989). Sex and the cerebral cortex. Biological Psychiatry 25, 823-825.

Driscoll, I., Hamilton, D.A., Yeo, R.A., Brooks, W.M. & Sutherland, R.J. (2005). Virtual navigation in humans: the impact of age, sex, and hormones on place learning. Hormones and Behavior 47(3), 326-335.

Edwards, J., Jackson, H.J. & Pattison, P.E. (2002). Emotion recognition via facial expression and affective prosody in schizophrenia: a methodological review. Clinical Psychology Review 22, 789-832. Erratum in: 2002, Clinical Psychology Review 22, 1267-1285.

Edwards, J., Pattison, P.E., Jackson, H.J. & Wales R.J. (2001). Facial affect and affective prosody recognition in first-episode schizophrenia. Schizophrenia Research 48(2-3), 235-253.

Epting, L.K. & Overman, W.H. (1998). Sex-sensitive tasks in men and women: a search for performance fluctuations across the menstrual cycle. Behavioral Neuroscience 112(6), 1304-1317. Fricchione, G., Sedler, M.J. & Shukla S. (1986). Aprosodia in eight schizophrenic patients. American Journal of Psychiatry 143(11), 1457-1459.

Gandour, J., Tong, Y., Wong, D., Talavage, T., Dzemidzic, M., Xu, Y., Li, X. & Lowe, M. (2004). Hemispheric roles in the perception of speech prosody. Neuroimage 23(1), 344-357.

Geschwind, N. & Galaburda, A.M. (1987). Cerebral lateralization: Biological mechanisms, associations and pathology. Cambridge, MA:MIT Press.

Page 56: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

56 Emotion recognition

Goldstein, J.M. & Lewine, R.R.J. (2000). Overview of sex differences in schizophrenia: where have we been and where do we go from here? In: Women and schizophrenia (ed. D.J. Castle, J.J McGrath & J. Kulkarni), pp 111-153. Mass. Cambridge University Press, Cambridge,

Goldstein, J.M., Cohen, L.S., Horton, N.J., Lee H., Andersen, S., Tohen, M., Crawford, A. & Tollefson G. (2002). Sex differences in clinical response to olanzapine compared with haloperidol. Psychiatry Research 110(1), 27-37.

Gur, R.E., Kohler, C., Ragland, J.D., Siegel, S.J., Bilker, W.B., Loughead, J., Phend, N. & Gur, R.C. (2003). Neurocognitive performance and clinical changes in olanzapine-treated patients with schizophrenia. Neuropsychopharmacology 28(11), 2029-2036.

Häfner, H., Maurer, K., Löffler, W., Fätkenheuer, B., Heiden, an der W., Riecher-Rössler, A., Behrens, S. & Gattaz, W. (1994). The epidemiology of early schizophrenia. Influence of age and gender on onset and early course. British Journal of Psychiatry 164, (Suppl 23) 29-38.

Häfner H. (2003). Gender differences in schizophrenia. Psychoneuroendocrinology 28 (Suppl 2), 17-54.

Halari, R., Mehrotra, R., Sharma, T., Ng, V. & Kumari, V. (2006). Cognitive impairment but preservation of sexual dimorphism in cognitive abilities in chronic schizophrenia. Psychiatry Research 141(2), 129-139.

Hall J.A. (1978). Gender effects in decoding non-verbal cues. Psychological Bulletin 85, 845-857.

Hall J.A. (1984). Non-verbal sex differences: Communication Accuracy and expressive style. Baltimore: John Hopkins University Press.

Halpern, D.F. & LaMay, L.M. (2000). The smarter sex: A critical review of sex differences in intelligence. Educational Psychology Review 12, 229-246.

Harvey, P.D., Napolitano, J.A., Mao L. & Gharabawi, G. (2003). Comparative effects of risperidone and olanzapine on cognition in elderly patients with schizophrenia or schizoaffective disorder. International Journal of Geriatric Psychiatry 18(9), 820-829.

Hooker, C. & Park, S. (2002). Emotion processing and its relationship to social functioning in schizophrenia patients. Psychiatry Research 112, 41-50.

Jordan, K., Wustenberg, T., Heinze, H.J., Peters, M. & Jancke, L. (2002). Women and men exhibit different cortical activation patterns during mental rotation tasks. Neuropsychologia 40(13), 2397-2408.

Page 57: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter two 57

Kay, S.R., Opler, L.A. & Fiszbein A. (1986). Positive and Negative Syndrome Scale (PANSS). MultiHealth Systems Inc. North Tonawanda, NY.

Kimura D. (1999). Sex and cognition. The MIT Press, Cambridge MA.

Kohler, C.G., Turner, T.H., Bilker, W.B., Brensinger, C.M., Siegel, S.J., Kanes, S.J., Gur, R.E. & Gur, R.C. (2003). Facial emotion recognition in schizophrenia: intensity effects and error pattern. American Journal of Psychiatry 160, 1768-1774.

Kucharska-Pietura, K., David, A.S., Dropko, P. & Klimkowski, M. (2002). The perception of emotional chimeric faces in schizophrenia: further evidence of right hemisphere dysfunction. Neuropsychiatry, Neuropsychology and Behavioral Neurology 15, 72-78.

Leentjens, A.F., Wielaert, S.M., van Harskamp, F. & Wilmink F.W. (1998). Disturbances of affective prosody in patients with schizophrenia; a cross sectional study. Journal of Neurology, Neurosurgery and Psychiatry 64(3), 375-378.

Leitman, D.I., Foxe, J.J., Butler, P.D., Saperstein, A., Revheim, N. & Javitt, D.C. (2005). Sensory contributions to impaired prosodic processing in schizophrenia. Biological Psychiatry 58(1), 56-61.

Leung, A. & Chue, P. (2000). Sex differences in schizophrenia, a review of the literature. Acta Psychiatrica Scandinavia (Suppl.) 101, 3-38.

Linn, M.C. & Petersen, A.C. (1985). Emergence and characterization of sex differences in spatial ability: a meta-analysis. Child Development 56(6),1479-1498.

Maki, P., Rich, J. & Rosenbaum, R.S. (2002). Implicit memory varies across the menstrual cycle: Estrogen effects in young women. Neuropsychologia 40, 518-529.

Mandal, M.K., Pandey, R. & Prasad A.B. (1998). Facial expressions of emotions and schizophrenia: a review. Schizophrenia Bulletin 24, 399-412.

McClure E.B. (2000). A meta-analytic review of sex differences in facial expression processing and their development in infants, children, and adolescents. Psychological Bulletin 126, 424-453.

Mitchell, R.L., Elliott, R., Barry, M., Cruttenden, A. & Woodruff, P.W. (2004). Neural response to emotional prosody in schizophrenia and in bipolar affective disorder. British Journal of Psychiatry 184, 223-230.

Moody, M.S. (1997). Changes in scores on the mental rotation test during menstrual cycle. Perceptual and Motor Skills 84, 955-961.

Page 58: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

58 Emotion recognition

Mueser, K., Doonan, R., Penn, D., Blanchard, J., Bellack, A., Nishith, P. & DeLeon, J. (1996). Emotion recognition and social competence in chronic schizophrenia. Journal of Abnormal Psychology 105, 271-275.

Muller, U., Werheid, K., Hammerstein, E., Jungmann, S. & Becker T. (2005). Prefrontal cognitive deficits in patients with schizophrenia treated with atypical or conventional antipsychotics. European Psychiatry 20(1), 70-73.

Murphy, D. & Cutting, J. (1990). Prosodic comprehension and expression in schizophrenia.Journal of Neurology, Neurosurgery and Psychiatry 53(9), 727-730.

Nelson, H.E. & Willison, J. (1982). National Adult Reading Test (NART), Second Edition.

Nestor, P.G., Han, S.D., Niznikiewicz, M., Salisbury, D., Spencer, K., Shenton, M.E. & McCarley, R.W. (2001). Semantic disturbance in schizophrenia and its relationship to the cognitive neuroscience of attention. Biological Psychology 57(1-3), 23-46.

Penn, D., Spaulding, W., Reed, D. & Sullivan, M. (1996). The relationship of social cognition to ward behaviour in chronic schizophrenia. Schizophrenia Research 20, 327-335.

Poole, J.H., Tobias, F. & Vinogradow S. (2000). The functional relevance of affect recognition errors in schizophrenia. Journal of the International Neuropsychological Society 6, 649-658.

Raven, J.C., Court, J.H. & Raven J. (1996). Standard progressive matrices: with adult US norms. Oxford: Oxford Psychologists; London: Lewis & Co.

Rilea, S.L., Roskos-Ewoldsen, B. & Boles D. (2004). Sex differences in spatial ability: a lateralization of function approach. Brain and Cognition 56(3), 332-343.

Roberts, J.E. & Bell, M.A. (2003). Two- and three-dimensional mental rotation tasks lead to different parietal laterality for men and women. International Journal of Psychophysiology 50(3), 235-246.

Ross, E.D., Orbelo, D.M., Cartwright, J., Hansel, S., Burgard, M., Testa, J.A. & Buck, R. (2001). Affective-prosodic deficits in schizophrenia: comparison to patients with brain damage and relation to schizophrenic symptoms [corrected]. Journal of Neurology, Neurosurgery and Psychiatry 70, 597-604. Erratum in: 2001, Journal of Neurology, Neurosurgery and Psychiatry 71, 283.

Rossell, S.L., Bullmore, E.T., Williams, S.C. & David A.S. (2002). Sex differences in functional brain activation during a lexical visual field task. Brain and Language 80(1), 97-105.

Page 59: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter two 59

Schirmer, A., Kotz, S.A., & Friederici, A.D. (2002). Sex differentiates the role of emotional prosody during word processing. Cognitive Brain Research 14(2), 228-233.

Schirmer A., Zysset S., Kotz S.A. & Yves von Cramon D. (2004). Gender differences in the activation of inferior frontal cortex during emotional speech perception. Neuroimage 21(3), 1114-1123.

Schmand, B., Lindeboom, J. & Harskamp, F. van. (1992). NLV: Nederlandse leestest voor volwassenen: handleiding (NLV) / Lisse: Swets & Zeitlinger.

Scholten, M., Aleman, A., Montagne, B. & Kahn R. (2005). Schizophrenia and processing of facial emotions: sex matters. Schizophrenia Research 78, 61-67.

Shaywitz, B.A., Shaywitz, S.E., Pugh, K.R., Constable, R.T., Skudlarski, P., Fulbright, R.K., Bronen, R.A., Fletcher, J.M., Shankweiler, D.P., Katz, L., et al. (1995). Sex differences in the functional organization of the brain for language. Nature 16;373(6515), 607-609. Comment in: Nature 1995,16;373(6515), 561-562.

Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R. & Dunbar G.C. (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59, 22-33.

Shepard, R.N. & Metzler, J. (1971). Mental rotation of three-dimensional objects. Science 171, 701-703.Siegel-Hinson, R.I. & McKeever, W.F. (2002). Hemispheric specialisation, spatial activity experience, and sex differences on tests of mental rotation ability. Laterality 7(1), 59-74.

Silverman, I. & Phillips, K. (1993). Effects of oestrogen changes during the menstrual cycle on spatial performance. Ethology and Sociobiology 4, 257-270.

Tong, Y., Gandour, J., Talavage, T., Wong, D., Dzemidzic, M., Xu, Y., Li ,X. & Lowe, M. (2005). Neural circuitry underlying sentence-level linguistic prosody. Neuroimage 28(2), 417-428.

Trauner, D.A., Ballantyne, A., Friedland, S. & Chase C. (1996). Disorders of affective and linguistic prosody in children after early unilateral brain damage. Annals of Neurology 39(3), 361-367.

Vingerhoets, G., Berckmoes, C. & Stroobant, N. (2003). Cerebral hemodynamics during discrimination of prosodic and semantic emotion in speech studied by transcranial Doppler ultrasonography. Neuropsychology 17(1), 93-99.

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Walder, D., Seidman, L., Cullen, N., Su, J., Tsuang, M. & Goldstein J. (2006). Sex differences in language dysfunction in schizophrenia. American Journal of Psychiatry 163, 470-477.

Weiss, E., Siedentopf, C.M., Hofer, A., Deisenhammer, E.A., Hoptman, M.J., Kremser, C., Golaszewski, S., Felber, S., Fleischhacker, W.W. & Delazer M. (2003). Sex differences in brain activation pattern during a visuospatial cognitive task: a functional magnetic resonance imaging study in healthy volunteers. Neuroscience Letters 344(3),169-172.

Woodruff, P.W., Wright, I.C., Bullmore, E.T., Brammer, M., Howard, R.J., Williams, S.C., Shapleske, J., Rossell, S., David, A.S., McGuire, P.K. & Murray R.M. (1997). Auditory hallucinations and the temporal cortical response to speech in schizophrenia: a functional magnetic resonance imaging study. American Journal of Psychiatry 154(12), 1676-1682.

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3Memory

Schizophrenia and sex differences in the simultaneous and sequential

processing of language and emotion.

Marion R.M. ScholtenAndré AlemanRené S. Kahn

Manuscript submitted for publication

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AbstractBackground: Emotion recognition and language processing have been found to be impaired in schizophrenia. These deficits have been associated with poorer social skills, although female patients show a more favorable course. We tested the hypothesis that male patients are more impaired in the simultaneous and se-quential processing of language and emotion than female patients. Method: Forty-eight patients with schizophrenia (24 m, 24 f), and 48 controls (24 m, 24 f) were assessed with 2 emotional working memory tasks and a visual emotional long-term memory task. One working memory task tested sensitivity to interference and required simultaneous operations in 2 conditions: counting while distinguishing between (i) male/female faces and between (ii) facial expres-sions (anger/fear). The other working memory task tested the capacity to main-tain and manipulate information and required sequential mental operations in 3 conditions: (i) simple arithmetic, (ii) distinction between male/female faces and (iii) between the facial expressions anger/fear. For each trial the participants were required to indicate whether the choice that had been made rhymed with a word presented subsequently on the screen (e.g. five-knife). The long-term memory task tested the ability to recognize pictures with a neutral, positive and negative content after 1 hour delay.Results: Male, but not female, patients were impaired on the emotion condition of the simultaneous working memory task. In contrast, on the emotion condition of the sequential working memory task, and on the long-term memory task, all patients were significantly impaired and no sex differences were observed. Conclusions: The findings suggest (1) that female patients are less sensitive to interference than male patients in the simultaneous processing of language and emotion, (2) that limitations in the capacity of the working memory and long-term memory to maintain and manipulate information are similar for both groups of patients.

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1. IntroductionOne of the most consistent findings in schizophrenia research are sex differences in course and outcome of the illness. Numerous studies have shown a less severe course and better preserved social skills in female patients compared to male pa-tients with schizophrenia (Goldstein, 2000; Häfner, 1994, 2003; Leung & Chue, 2000). Although the cause of sex differences in schizophrenia is still unknown, normal sexual dimorphism of the brain, with slower maturation and more asym-metry in male brain structures, mediated by prenatal effects of sex steroid hor-mones, has been hypothesized to underlie the differences in the manifestation of the illness (Collaer & Hines, 1995; Diamond, 1989; Geschwind & Galaburda, 1987). In healthy subjects, dimorphic brain functioning has been related to sex differences in performance on cognitive and emotional tasks. For example, wom-en have been found to outperform men in emotion recognition (Hall, 1978, 1984; McClure, 2000), and in language processing (Halpern & LaMay, 2000; Kimura, 1999), both crucial for successful social interaction, and men to excel in visuo-spatial tasks (Linn & Petersen, 1985; Roberts & Bell, 2003).

In patients with schizophrenia, various domains of cognitive and emotional processing, such as emotion recognition (Edwards et al., 2001, 2002), language processing (Condray et al., 2002; Nestor et al., 2001; Walder et al., 2006) and memory function (Barch, 2005; Goldberg et al., 2003) are known to be impaired. These difficulties have been found to be associated with poorer social skills and im-poverished interpersonal relations (Hooker & Park, 2002; Penn et al., 1996; Poole et al., 2000; Zanello et al., 2006). Since the female advantage in facial emotion recognition (Scholten et al., 2005) and language processing (Walder et al., 2006) has been shown to be preserved in female patients with schizophrenia, the high-er level of social functioning in female patients has been suggested to be in part the result of the preservation of this advantage (Scholten et al., 2005). However, daily life functioning rarely implies doing one thing at a time, but requires multi-tasking, such as for instance the simultaneous and sequential processing of lan-guage and emotion. These activities strongly depend on long-term memory and working memory function, e.g. recognition, selection, (temporary) storage and integration of information (Baddely et al., 1994). Therefore, to study sex differ-ences in a more ‘real-world’ situation, it is important to assess participants with tasks that require processing of language and emotion at the same time.

Although in schizophrenia the storage systems in working memory for verbal and visual information have been found to be relatively intact, numerous studies have shown impairment of the ‘central executive’ component of the working mem-ory, which is supposed to be an active control system involved in the manipula-tion of information such as encoding, updating and protection from interference (for an overview see Barch, 2005, 2006). Patients with schizophrenia have been reported to be limited in working memory capacity (Goldman-Rakic 1994; Jans-ma et al. 2004; Pukrop et al., 2003; Silver et al., 2003) and to be unable to re-cruit additional resources in case of competing demands (Kathman et al., 1995). Besides deficits in working memory, in schizophrenia also impairment in long-term memory, especially in visual memory, has been found, which has been as-

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sociated with impoverished social outcome (Jaeger & Douglas, 1992; Kerr et al., 1992; Mueser et al., 1991, 1996).

In healthy subjects, findings on sex differences in working memory function-ing are inconsistent. Several studies have reported that women excel in verbal working memory tasks and that men outperform women in tasks of visuo-spatial ability (Boone & Lu, 2000; Halpern & LaMay, 2000; Rahman et al., 2005). Other studies do not find sex differences in performance at all (Haut & Barch, 2006). Furthermore, recent findings from functional Magnetic Resonance Imaging (fMRI) research suggest that men and women activate different brain areas when engag-ing in various working memory tasks, but do not differ in performance (Speck et al., 2000). On long-term memory, gender differences have been reported in ver-bal memory tasks, such as word recall and recognition (Berenbaum et al., 1997; Herlitz et al., 1997) and story recall (Hultsch et al., 1991), with women outper-forming men. An fMRI study by Lang et al., (1998) on visual emotional memory, showed greater activity in female subjects for processing pictures with a nega-tive emotional content, and greater activity in male subjects while processing pic-tures with a positive emotional content.

Thus, to sum up, impairment in social skills is more severe in male patients with schizophrenia relative to female patients and has been associated with dys-function in cognitive and emotional processing, while in healthy subjects sex differ-ences, favoring women, have been reported in language processing and emotion recognition. Since social interaction in daily life requires the concurrent process-ing of language and emotion, we aimed to investigate whether female patients would outperform male patients on a set of visual and verbal working memory and long-term memory tasks, with and without emotional content.

Because women are already known to excel in emotion recognition (Hall, 1978; 1984; McClure et al., 2000) and verbal processing (Halpern & LaMay, 2000; Kimu-ra, 1999), we predicted female patients to outperform male patients on 2 differ-ent emotional working memory tasks simultaneously and sequentially processing language and emotion. The first task measures sensitivity to interference in a dual task paradigm, the other task measures the capacity to maintain and ma-nipulate (compare) emotional and verbal information

On the long-term memory task, pictures with positive emotions were expect-ed to be recalled better than negative or neutral pictures (Danion et al., 2003). Since there is evidence that the emotional valence of stimuli may have different effects on memory in men and women (Lang et al., 1998), we predicted female patients to outperform male patients in recognizing pictures with a negative emo-tional content, and male patients to excel in recognizing pictures with a nega-tive emotional content.

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2. Method 2.1. ParticipantsForty-eight patients with schizophrenia (24 men, 24 women) and 48 healthy con-trols (24 men, 24 women), all native Dutch speakers, participated in this study. All patients attended the out-patient clinic of the Schizophrenia Research Unit at the Utrecht University Hospital. The psychiatric diagnosis had been confirmed by an independent psychiatrist via a structured diagnostic interview (the Compre-hensive Assessment of Symptoms and History; Andreasen et al., 1992). All pa-tients satisfied the DSM-IV-R criteria for schizophrenia.

To avoid any effects of affective symptoms and co-medication on the scores, only patients without prominent affective symptoms (e.g. no schizo-affective dis-order, no concurrent depression) and no other concomitant axis I disorder were recruited for the study. Most female (n= 22) and male (n=20) patients were di-agnosed with the paranoid subtype of schizophrenia. Only 1 female patient and 2 male patients were diagnosed with a disorganized subtype, 1 male and 1 fe-male patient with an undifferentiated subtype, and 1 male patient with a residu-al subtype. At the time of testing, all patients were taking atypical antipsychotics without any co-medication, such as tranquilizers, antidepressants, and anticholin-ergics, since medication with sedative or anticholinergic properties may adverse-ly affect memory (Blanchard & Neale, 1992; Spohn & Strauss, 1989). Patients were studied while at least 6 weeks clinically stable on the same dosage of an-tipsychotics.

Positive and negative symptoms, including their severity, were measured with a structured interview (the Positive And Negative Syndrome Scale (PANSS); Kay et al., 1986), on the day of testing.

Male and female patients did not differ significantly in age at first psychosis, the number of hospitalizations, the duration of illness and the dosage of their medication.

The control subjects were either volunteers from the Utrecht University Hos-pital or had been recruited through advertisements in local newspapers. They had been screened, using the Mini-International Neuropsychiatric Interview Plus (MINI-Plus), for current or past psychiatric illness in themselves and in their first-degree relatives (Sheehan and Lecrubier, 1998).

All participants were assessed with the Dutch version (Nederlandse Leestest voor Volwassenen, NLV; Schmandt et al., 1992) of the National Adult Reading Test (NART; Nelson & Willison, 1982), a test devised to predict pre-morbid intellec-tual functioning in subjects suspected of cognitive decline. The test is composed of a list of 50 non-phonetic words (i.e. pronunciation does not follow the normal phonetic rules), printed in order of increased difficulty. The subject is required to read these words aloud; scores are based on the number of errors made in pro-nunciation. Scores on the Raven Standard progressive matrices (Raven et al., 1996) were used as an index for nonverbal, performal IQ.

Both groups were screened using a medical history questionnaire and inter-view. Exclusion criteria included a history of neurological or systemic disease, and a diagnosis of an active substance use disorder in the 3 months prior to study.

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In order to avoid any effects of the menstrual cycle, all female participants were tested in the first 10 days of their cycle (starting from day 1 of menstru-ation). Patients and control subjects did not differ significantly in terms of edu-cation, pre-morbid estimated IQ (NART), or age within sex, but differed in age between groups and in non-verbal IQ (Raven).

Group characteristics of patients and controls are reported in Table 1.

After receiving a complete description of the study, written informed consent was obtained from the subjects. The study had been approved by the Medical Ethics Committee of the University Medical Center Utrecht.

2.2.Materials 2.2.1. Simultaneous Working Memory taskThe Simultaneous Working Memory task consisted of 30 randomly ordered pic-tures (15 male, and 15 female faces) in 2 conditions. In condition 1, all subjects were presented with a series of 30 pictures on a computer screen. By pressing a left or right button on the keyboard, subjects had to indicate whether the face was male or female, while simultaneously counting loud from 1 to 10, over and over again. In condition 2 (emotion-condition) subjects had to decide whether the fa-cial expression of the 30 pictures was anger or fear, while counting out loud from 1 to 10. The testing of both conditions was preceded by 4 practice trials.

2.2.2. Sequential Working Memory task The Sequential Working Memory task consisted of 3 subtasks with 16 items each.

In de first condition subjects were presented with 16 sums on a computer screen (for example 3 + 3), which they had to work out. After 2 seconds the sum was replaced with a word (for example ‘mes’ (= knife)) and participants were asked to indicate (by pressing a left (= no) or right (= yes) button) if the an-swer they had worked out (6 = ‘zes’ (six)), rhymed with the word presented on the screen (‘mes’).

In the second condition, a face of a man or a woman was shown during 2 sec-onds, on a computer screen. Subjects had to decide if the face was male or fe-male and were asked to indicate, by pressing a left or right button, whether the word presented on the computer screen rhymed with ‘man’(= man) or ‘vrouw’ (= woman), for example man-pan or vrouw-blauw (= blue).

In the third condition, a face of a man or woman was shown during 2 sec-onds, expressing the emotion fear or anger. Again, participants had to decide if the word that was presented on the computer screen rhymed with the emotion that was shown (for example ‘bang’ (= fear) with ‘lang’ (= long), or ‘boos’ (= an-ger) with ‘roos’ (= rose)).

In all three conditions (arithmetic, male-female faces and fear-anger recogni-tion) subjects were first presented with 4 practice trials, followed by 16 random-ly ordered trials of each condition.

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Table 1. Characteristics of all participants of the Simultaneous Working Memory task, Long-term Memory task and Sequential Working Memory task*

Characteristic Male patients(N=24/21*)

Female Patients(N=24/20*)

Male controls(N=24/20*)

Female controls(N=24/21*)

Mean SD Mean SD Mean SD Mean SD

Age (years) 29.0/28.5(19-40 y)

6.8/7.1

32.1/33.1(20-39 y)

6.5/6.2

26.9/26.4(19-41 y)

6.1/5.9

28.7 /29.5(20-39 y)

6.2/6.2

Subjects’ education (1) 2.1/2.0

1.0/.9

2.5/2.5

.8/

.92.5/2.5

.8/

.92.5/2.4

.8/

.8

NART 107.0/105.6

9.8/9.9

110.8/110.6

8.2/8.9

108.8/108.3

5.8/5.9

107.4/105.8

6.8/6.4

Raven 8.0/8.3

2.8/2.7

9.1/9.1

2.0/1.8

9.6/9.5

2.0/1.9

9.6/9.3

1.9/1.8

PANSS Positive Syndrome scale scores(2)

11.2/11.3

4.1/3.7

10.3/10.9

3.7/3.8

PANSS Negative syndrome scale scores(2)

16.3/16.4

6.9/7.1

13.8/13.9

5.0/5.2

PANSS General symptom scores(2)

26.1/25.1

8.1/7.1

24.8/26.5

5.4/4.2

Duration of illness (years) (2)

6.4/6.5

4.2/4.7

8.2/8.3

6.6/6.5

Age at first psychosis(2)22.6/22.0

5.4/5.3

23.9/24.8

5.6/5.8

Number of hospitalizations(2)

1.6/1.6

1.2/1.3

1.2/1.3

1.3/1.3

Dose of atypical antipsychotics(2,3)

12.8/14.2

5.1/5.6

11.9/13.6

6.3/7.3

*Not all subjects participated in both tasks(1) Education was measured on a 4-point scale: low (1); middle (2); high (3); university (4).(2) Differences between male and female patients were non-significant(3) Dose of atypical antipsychotics in mg olanzapine equivalents (Dose conversion: 20

mg of olanzapine is equivalent to 6 mg of risperidone, 700 mg of quetiapine, 30 mg aripiprazole or 500 mg of clozapine; ref.: Kohler et al., 2003); Olanzapine (N=19; range = 5-20 mg; mean dose 10 mg); Clozapine (N=10; range = 250-600 mg; mean dose 325 mg = 13 mg equivalent olanzapine); Risperidone (N= 10; range = 1.5-6 mg; mean dose 3.65 mg = 12 mg equivalent olanzapine); Quetiapine (N=2; mean dose 400 mg = 11 mg equivalent olanzapine); Aripiprazole (N= 7 ; range = 15-30 mg; mean dose 20 mg = 13 mg equivalent olanzapine)

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2.2.3. Long-term Memory taskAll participants were shown seventy-two images (24 with neutral, 24 with posi-tive and 24 with negative valence), selected from the International Affective Pic-ture System (IAPS; Lang et al., 1997), in random order on a computer screen. The IAPS are a set of stimuli with normative emotional valence ratings for each image, ranging from 1 (the most negative) to 9 (the most positive) on a Likert-type rating scale. Valence levels and arousal levels of all images were balanced for neutral, positive and negative pictures.

Following this initial presentation, participants completed several question-naires (NART, Raven) and were assessed with the Simultaneous Working Memo-ry task and the Sequential Working Memory task. After 1 hour all subjects were shown again 72 pictures, half of which had been viewed previously and half of which were novel. Participants were asked to endorse whether the image present-ed was novel or had been presented previously by pressing a left or right button. After responding, the next image would appear.

2.4. Statistical analysisThe data of the Simultaneous Working Memory task were analyzed by a three-way within subjects ANCOVA (Task, Sex and Group) contrasting the emotional and neutral conditions. Age and IQ were included as covariates. In addition, scores on the 3 sub-tests of the Sequential Working Memory task (arithmetic, male-fe-male faces, anger-fear recognition) and on the Long-term Memory task were an-alyzed by MANOVA. To contrast the Simultaneous Working Memory task with the Sequential Working Memory task, a repeated measures analysis was conducted with age as a covariate.

Correlation coefficients (Pearson) were computed for associations between data and patient variables (duration of illness, number of hospitalizations, dos-age of medication, PANSS-scores). Results were regarded significant at a con-ventional level of alpha = .05, two-tailed.

3. Results3.1. Clinical variablesAs can be seen in Table 1, no significant differences were found in the patient groups between men and women in severity of negative symptoms, positive symp-toms and general psychopathology sub-scale, measured by the PANSS.

3.2. Simultaneous Working Memory task scoresThe ANCOVA on the emotional and neutral condition of the Simultaneous Work-ing Memory task scores revealed significant effects for Sex (F(df 1,92) = 5.9; p = .018), with higher scores in women than in men, and for Group (F(df 1,92) = 9.8; p = .002), with higher scores in controls than in patients. In addition, a sig-nificant interaction between Group and Sex was observed (F(df 1.92) = 4.6; p = .034), which revealed that the sex difference was specific for patients, with low-

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er scores in male patients, but not in female patients, while no differences were found between male and female controls.

Within-Subjects effects in the emotion condition versus the control condition were found to be significant for Condition x Sex (F(df 1,92) = 5.1; p = .026), for Condition x Group (F(df 1,92) = 4.3; p = .042), and for Condition x Sex x Group (F(df 1,92) = 4.7; p = .033). On the neutral condition all subjects obtained similar scores, but on the emotion condition only male patients scored significantly lower than the other 3 groups. There was no significant effect of age or IQ (Raven).

No correlations were found between scores on the Simultaneous Working Mem-ory task, PANSS-scores, duration of illness, or number of hospitalizations. Lower scores on the Simultaneous Working Memory task correlated with higher dos-age of medication (r = -343; p= .017). Although dosage of medication did not differ significantly between male and female patients, a separate analysis was performed with dosage of medication as a covariate. This revealed a significant effect on task (F(df 1,45) = 7.0; p = .011) and a significant effect of Sex (F(df 1,45) = 8.0; p = .007).

3.3. Sequential Working Memory task scoresA MANCOVA on all three Sequential Working Memory task conditions combined, with IQ (Raven) as a covariate, revealed a significant effect of Group (F(df 3,75) = 2.9; p = .043), controls performing better than patients, but not of Sex (F(df 3,75) = .5; p = .682) and no interaction (F(df 3,75) = 1.0; p = .411). There was also a significant effect of IQ, F(df 3,75) = 8.8; p < .001). Post-hoc analysis showed that the Group effect was specific for the subtask Emotion (distinguishing fear/anger), F(df 1,77) = 5.8 (p = 0.018), indicating that control subjects performed better than patients. The subtask Faces (distinguishing male/female faces) showed a marginally significant effect for Group (F( df 1,77) = 3.7; p = .057).

Reaction Time data of the Sequential Working Memory task, all three condi-tions combined, showed a trend for Group (F(df 3,76) = 2.2; p = .090), controls performing faster than patients, but not for Sex (F(df 3,76) = 1.8; p = .161), and no interaction (F(df 3,76) = .2; p = .924). No significant effect of age or IQ (Raven) was found on the Reaction Time data. No correlations were found be-tween scores on the Sequential Working Memory task, PANSS-scores, duration of illness, number of hospitalizations, or dosage of medication.

3.4. Contrasting Simultaneous Working Memory data and Sequen-tial Working Memory dataBecause the above analyses suggest that women with schizophrenia perform as well as controls on the simultaneous but not sequential Working Memory task, in contrast to men with schizophrenia (who perform worse on both tasks relative to controls), we conducted a direct comparison of gender and group for both tasks in the emotion condition, using repeated measures ANOVA. Between-Subject effects were found to be significant for Sex (F(df 1,78) = 4.1; p = .046), with higher scores in women than in men, for Group (F(df 1,78) =

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14.5; p < .001), controls performing better than patients, and for Sex x Group (F(df 1,78) = 4.9; p = .031).

Significant Within-Subjects effects were found for Task x Sex (F(df 1,78) = 5.4; p = .022), but not for Task x Group (F(df 1,78) = 0.4; p = .510), and for Task x Sex x Group (F(df1,78) = 5.2; p = .026). The Task x Sex x Group interac-tion confirms that the sex difference in schizophrenia is different for the Simul-taneous and the Sequential Working Memory tasks.

Age as a covariate had no effect.

3.5. Long-term Memory task scoresA MANCOVA on all pictures combined, with IQ (NART) as a covariate, showed a significant effect of IQ (F (df 3,89) = 4.9; p = .003) on task performance, a sig-nificant effect of Group (F (df 3,89 = 7.3; p < .001), with controls performing better than patients, but no effect of Sex and no Group x Sex interaction. Post-hoc analyses of the separate scores on pictures with positive, negative and neu-tral content showed a significant effect of Group for positive (F (df 1,91) = 8.1; p = .005), negative (F (df 1,91) = 17.6; p <.001) and neutral (F (df 1.91) = 16.2; p < .001) content, with lower scores in patients than in controls.

Table 2 and 3 show the accuracy scores of Woking Memory and Long-term Mem-ory tasks.

4. DiscussionThis study examined sex differences in long-term memory and working mem-ory function in patients with schizophrenia and control subjects with the use of novel tasks. Since women outperform men in emotion recognition (Hall, 1978, 1984; McClure, 2000) and language processing (Halpern & LaMay, 2000; Kimu-ra, 1999), both vital for social functioning in daily life, they were expected also to excel in tasks combining the processing of language and emotion. In addi-tion, we expected this female advantage to be preserved in female patients with schizophrenia, since they have been shown better preserved skills than male pa-tients (Goldstein & Lewine, 2000; Häfner et al., 1994; Leung & Chue, 2000). Our findings revealed that men, but not women, with schizophrenia were significant-ly impaired in simultaneously processing language and (facial) emotion. In con-trast, male and female patients were found to be equally impaired in long-term memory and in sequential working memory processing of emotional and neutral, visual and verbal stimuli. In sequential processing of mathematics and language, patients and controls obtained similar scores.

The Simultaneous and Sequential Working Memory tasks have both been as-sociated with the central executive function of the working memory, such as di-viding attention and protection from interference in the Simultaneous Working Memory task, and the ability to hold information online and manipulate this in-formation in the Sequential Working Memory task. Furthermore, in the Sequen-tial task, also short term storage for visual information is required.

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Table 2. Accuracy scores of the Simultaneous Working Memory task and the Long-term Memory task

Characteristic Male

patients

(N=24)

Female

patients

(N=24)

Male

controls

(N=24)

Female

controls

(N=24)

Accuracy Mean SD Mean SD Mean SD Mean SD

Simultaneous

WM task

Control

condition

(face man/

woman)

29.1

(range

27-30)

.9 29.3

(range

27-30)

.9 29.5

(range

28-30)

.7 29.5

(range

24-30)

1.3

Control

condition

Reaction time

922.4 412.7 890.2 313.6 747.3 188.5 757.6 127.2

Emotion

condition

(anger/afraid)

25.7

(range

18-30)

2.8 27.7

(range

24-30)

1.6 27.8

(range

24-30)

1.7 27.9

(range

23-30)

1.5

Emotion

condition

Reaction time

1372.9 418.7 1573.4 708.6 1116.5 331.7 1362.0 525.4

Emotional

long-term

Memory taskAll conditions 64.0

(range

52-72)

4.9 64.8

(range

51-70)

4.9 67.8

(range

59-72)

3.6 68.5

(range

61-72)

2.8

RT 1235.5 234.7 1278.0 397.1 1161.1 199.4 1256.4 321.5

Positive

content

21.4

(range

17-24)

2.1 21.7

(range

18-24)

1.8 22.3

(range

19-24)

1.5 22.7

(range

21-24)

1.1

RT 1291.1 276.4 1305.1 415.7 1150.7 239.5 1247.0 323.7

Negative

content

21.8

(range

16-24)

2.0 21.2

(range

16-24)

2.0 22.8

(range

19-24)

1.3 23.1

(range

18-24)

1.4

RT 1232.2 229.1 1316.3 454.3 1209.5 213.3 1355.7 374.4

Neutral content 20.9

(range

17-24)

2.1 22.0

(range

15-24)

2.1 22.7

(range

19-24)

1.3 22.7

(range

19-24)

1.2

RT 1165.05 255.4 1170.2 4351.0 1120.0 209.1 1203.4 344.5

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74 Memory

The Simultaneous Working Memory task that was used in this study (count-ing out loud from 1 to 10), is relative easy and will not require major attention or cause overload of available resources, but only leads to little interference with fa-cial (emotion) recognition in healthy subjects. However, when resources are lim-ited because of compromised working memory subsystems, the attentional load available for stimulus evaluation may become too low. In our study, on the con-trol condition of the Simultaneous Working Memory task, all participants scored equally well, but on the emotion condition only male patients showed impairment, while female patients reached the same accuracy scores as comparison subjects. Since women have been found to excel in facial emotion perception, and to pre-serve that advantage in schizophrenia (Scholten et al., 2005), female patients may need less working memory capacity to process facial emotions. Therefore, one could argue that their superior performance relative to male patients on the Simultaneous Working Memory task may in part be attributed to a female advan-

Table 3. Accuracy scores of the Sequential Working Memory task

Characteristic Male patients

(N=21)

Female patients

(N=20)

Male controls

(N=20)

Female controls

(N=21)

Sequential WM

Task

Mean SD Mean SD Mean SD Mean SD

Accuracy

Faces

(men/women)

15.3

(range

13-16)

1.0 15.4

(range

13-16)

.9 15.6

(range

14-16)

.8 15.8

(range

14-16)

.5

RT

Faces

(men/women)

1429.0 565.3 1600.4 767.3 1132.3 295.3 1414.3 492.4

Accuracy

Arithmetic

13.7

(range

7-16)

2.4 14.4

(range

11-16)

1.4 15.1

(range

13-16)

.9 14.2

(range

10-16)

2.0

RT

Arithmetic

2187.1 1026.1 3291.8 3951.6 1509.9 404.4 2410.0 2687.2

Accuracy

Emotion

(anger/afraid)

14.4

(range

8-16)

2.1 14.5

(range

10-16)

1.8 15.4

(range

13-16)

.8 15.3

(range

14-16)

.7

RT

Emotion

(anger/afraid)

1484.3 572.5 1608.8 729.0 1228.3 260.8 1399.4 463.2

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tage in emotion recognition. However, in contrast to previous studies with emotion perception tasks, in this task only two emotions (anger, fear) had to be distin-guished, which made the task relatively easy to perform. Furthermore, while the same faces and the same two emotions were used in the Simultaneous Working Memory task as well as in the Sequential Working Memory task, male and female patients performed equally well (but significantly worse than controls) on the emo-tion condition of the Sequential Working Memory task. This may indicate that sex differences in the ability of emotion recognition are not a crucial (nor a confound-ing) factor in explaining the sex difference between male and female patients in the Simultaneous Working Memory task. Another explanation might be that men and women activate different brain areas in completing working memory tasks. For example, Speck et al., (2000) found right-lateralized or bilateral activation in male subjects, and predominantly left hemispheric activation in female subjects in a verbal working memory task, in the absence of sex differences in perform-ance. Simultaneously performing a facial emotion recognition task (which is sup-posed to be right lateralized) and a verbal working memory task (relatively left lateralized in women, and right lateralized in men), might cause more interfer-ence in men than in women, and result in impaired performance in male patients when working memory capacity is compromised by schizophrenia.

On the Sequential Working Memory task, all participants subsequently had to identify and hold on line 3 types of information (mathematics, male-female faces and the facial emotions anger-fear) and to compare that information with verbal material. Patients performed significantly worse relative to controls on facial emo-tions, but not on mathematics. These findings indicate that especially the process-ing of emotions is impaired in schizophrenia. This might be due to the fact that schizophrenia has been associated with dysfunction of right hemisphere regions involved in emotion processing (Borod et al., 1993; Cutting, 1992; Kucharska-Pi-etura et al., 2002; Ross et al., 2001), while processing mathematics and seman-tics are both more left lateralized. Since no sex differences were observed in the Sequential Working Memory task, this might imply that women do not benefit from their advantage in emotion recognition when more complex working mem-ory activities are required.

In line with previous studies on verbal (Berenbaum et al., 1997; Herlitz et al., 1997) and visual (Aleman et al., 1999) memory in schizophrenia, in our study controls were found to outperform patients in recognizing all three types of pic-tures (positive, negative and neutral) of the visual emotional Long-term Memo-ry task. This may suggest a more generalized memory deficit in patients than a specific deficit in processing emotion. Our prediction that women would outper-form men in recognizing pictures with a negative emotional content, and that men would outperform women in recognizing pictures with a positive emotional content, was not confirmed. Type of emotion that was shown in the picture (pos-itive or negative) did not make any difference in accuracy scores between the sexes. This might in part be due to the fact that recognition of the pictures was required, not of the type of emotion itself.

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A noteworthy strength of this study is the care that was taken to avoid con-founding effects of symptom severity, because female patients generally present with later age at onset and less severe (negative) symptoms than male patients. Indeed, we can be confident that the sex differences we found, cannot be attribut-ed to sex differences in severity of illness, because age at onset, severity of symp-toms and dosage of medication did not show significant differences between male and female patients. Duration of illness even tended to be longer in women than in men. A limitation might be that the sample was a selective sample, consisting of stabilized outpatients on atypical antipsychotics, without co-medication, recent drug abuse or co-morbid affective symptoms. Despite this fact, in the majority of our tasks, significant differences between patients and controls were observed. A second limitation might be that the tasks were easy to perform. Especially in the control subjects this may have caused ceiling effects, obscuring potential sex differences (for example in the Simultaneous Working Memory task).

In summary, men, but not women, with schizophrenia were significantly im-paired in performing a simultaneous language/emotion working memory task. Because simultaneously processing visual and verbal information is crucial in so-cial interaction, this may explain, in part, why male patients with schizophrenia show poorer social skills than female patients. Future studies should investigate such a putative relationship directly by including reliable measures of every-day social functioning. However, in more complex sequential or long-term process-ing of visual and verbal, emotional and neutral stimuli, no female advantage was observed, and limitations in the capacity of the working memory and long-term memory were found to be similar for male and female patients.

Finally, given the impaired performance in patients on all tasks involving emo-tional stimuli, our results confirm the accumulating evidence that schizophrenia is pre-eminently an emotional disorder (Aleman & Kahn, 2005).

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5. ReferencesAleman, A., Hijman, R., Haan, E.H. de, Kahn, R.S., 1999. Memory impairment in schizophrenia: a meta-analysis. Am. J. Psychiatry 156(9),1358-1366.

Aleman, A., Kahn, R.S., 2005. Strange feelings: do amygdala abnormalities dysregulate the emotional brain in schizophrenia? Progress in Neurobiology 77(5), 283-298.

Andersen, N.C., Flaum, M., Arndt, S., 1992. The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Arch. Gen. Psychiatry 49, 615-623.

Baddeley, AD., 1994. Working memory: the interface between memory and cognition. In: Schacter, D.L., Tulving, E. (Eds), Memory Systems. MIT Press, Cambridge, MA, pp 351-367.

Barch, D.M., 2005. The cognitive neuroscience of schizophrenia. Annu. Rev. Clin. Psychol. 1, 321-353.

Barch, D.M., 2006. What can research on schizophrenia tell us about the cognitive neuroscience of working memory? Neuroscience 139, 73-84.

Berenbaum, S., Baxter, L., Seidenberg, M., Hermann, B., 1997. Role of the hippocampus in verbal memory outcome following left anterior temporal lobectomy. Neuropsychology 11, 585-591.

Blanchard, J.J., Neale, J.M., 1992. Medication status of participants in psychopathology research: selective review of current reporting practices. J. Abnorm. Psychol. 101(4), 732-734.

Boone, K., Lu, P., 2000. Gender effects in neuropsychological assessment. In: Fletcher-Janzen, E., Strickland, T., Reynolds, C. (Eds.), Handbook of cross-cultural neuropsychology, New York, NY: Kluwer Academic/Plenum Publishers, pp 73-86.

Borod, J.C., Martin, C.C., Alpert, M., Brozgold, A., Welkowitz, J., 1993. Perception of facial emotion in schizophrenic and right brain-damaged patients. J. of Nerv. Ment. Dis. 181, 494-502.

Collaer, M.L., Hines, M., 1995. Human behavioral sex differences: a role for gonadal hormones during early development? Psychological Bull. 118(1), 55-107.

Condray, R., Steinhauer, S.R., van Kammen, D.P., Kasparek A., 2002. The language system in schizophrenia: effects of capacity and linguistic structure. Schizophr. Bull. 28(3), 475-490.

Page 78: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

78 Memory

Cutting, J. (1992). The role of right hemisphere dysfunction in psychiatric disorders. Br. J. Psychiatry 160, 583-588.

Danion, J-M., Kazes, M., Huron, C., Karchouni, N., 2003. Do patients with schizophrenia consciously recollect emotional events better than neutral events? Am. J. Psychiatry 160, 1879-1881.

Diamond, M.C., 1989. Sex and the cerebral cortex. Biol. Psychiatry 25, 823-825.

Edwards, J., Jackson, H.J., Pattison, P.E., 2002. Emotion recognition via facial expression and affective prosody in schizophrenia: a methodological review. Clin. Psychol. Rev. 22, 789-832. Erratum in: 2002, Clin. Psychol. Rev. 22, 1267-1285.

Edwards, J., Pattison, P.E., Jackson, H.J., Wales R.J. (2001). Facial affect and affective prosody recognition in first-episode schizophrenia. Schizophr. Res. 48(2-3), 235-253.

Geschwind, N., Galaburda, A.M., 1987. Cerebral lateralization: Biological mechanisms, associations and pathology. Cambridge, MA:MIT Press.

Goldberg, T., David, A., Gold, J., 2003. Neurocognitive deficits in schizophrenia. In: Hirsch, S., Weinberger, D. (Eds.), Schizophrenia. Blackwell Science Ltd, 9600 Garsington Road, Oxford OX42DQ, UK, pp168-184.

Goldman-Rakic, P. 1994. Working memory dysfunction in schizophrenia. J. Neuropsychiat. Cli. Neurosc. 6, 348-357.

Goldstein, J.M., Lewine, R.R.J., 2000. Overview of sex differences in schizophrenia: where have we been and where do we go from here? In: Castle, D.J., McGrath, J.J. & Kulkarni, J. (Eds.), Women and schizophrenia. Mass. Cambridge University Press, Cambridge, pp 111-153.

Häfner, H., Maurer, K., Löffler, W., Fätkenheuer, B., Heiden, an der W., Riecher-Rössler, A., Behrens, S., Gattaz, W., 1994. The epidemiology of early schizophrenia. Influence of age and gender on onset and early course. Br. J. Psychiatry 164 (Suppl 23), 29-38.

Häfner, H., 2003. Gender differences in schizophrenia. Psychoneuroendocrinology Suppl 2, 17-54.

Hall, J.A., 1978. Gender effects in decoding non-verbal cues. Psychol. Bull. 85, 845-857.

Hall, J.A., 1984. Non-verbal sex differences: Communication Accuracy and expressive style. Baltimore: John Hopkins University Press.

Halpern, D., LaMay, L., 2000. The smarter sex: A critical review of sex differences in intelligence. Educational Psychology Review 12, 229-246.

Page 79: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter three 79

Haut, K.M., Barch, D.M., 2006. Sex influences om material-sensitive functional lateralization in working and episodic memory: Men and women are not all that different NeuroImage 32, 411-422.

Herlitz, A., Nilsson, L., Backman, L., 1997. Gender differences in episodic memory. Memory & Cognition 25, 801-811.

Hooker, C., Park, S., 2002. Emotion processing and its relationship to social functioning in schizophrenia patients. Psychiatry Res. 112, 41-50.

Hultsch, D.F., Masson, M.E., Small, B.J., 1991. Adult age differences in direct and indirect tests of memory. J. Gerontol. 46(1), 22-30. Erratum in: J. Gerontol. 1991 46(6), 339.

Jaeger, J., Douglas, E., 1992. Neuropsychiatric rehabilitation for persistent mental illness. Psychiatr. Q. 63, 71-94.

Jansma, J.M., Ramsey, N.F., van der Wee, N.J., Kahn, R.S., 2004. Working memory capacity in schizophrenia: a parametric fMRI study. Schizophr. Res. 68(2-3), 159-171.

Kathmann, N., Wagner, M., Rendtorff, N., Schochlin, C., Engel, R.R., 1995. Information processing during eye tracking as revealed by event-related potentials in schizophrenics, alcoholics, and healthy controls. Schizophr. Res. 16(2), 145-156.

Kay, S.R., Opler, L.A., Fiszbein, A., 1986. Positive and Negative Syndrome Scale (PANSS). MultiHealth Systems Inc. North Tonawanda, NY.

Kerr, R., Green, M., Satz, P., 1992. Neuropsychological predictors of skills training for chronic psychiatric patients. Psychiatry Res. 43, 223-230.

Kimura, D., 1999. Sex and cognition. The MIT Press, Cambridge MA.

Kucharska-Pietura, K., David, A.S., Dropko, P., Klimkowski, M., 2002. The perception of emotional chimeric faces in schizophrenia: further evidence of right hemisphere dysfunction. Neuropsychiatry, Neuropsychology and Behavioral Neurology 15, 72-78.

Lang, P., Bradley, M., Fitzsimmons, J., Cuthbert, B., Scott, J., Moulder, B., Nangia, V., 1998. Emotional arousal and activation of the visual cortex: An fMRI analysis. Psychophysiology 35, 1-13.

Lang, P.J., Bradley, M.M., Cuthbert, B.N., 1997. International Affective Picture System (IAPS); Technical Manual and Affective Ratings. NIMH Center for the Study of Emotion and Attention.

Leung, A., Chue, P., 2000. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr. Scand. (Suppl.)101, 3-38.

Page 80: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

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Linn, M.C., Petersen, A.C., 1985. Emergence and characterization of sex differences in spatial ability: a meta-analysis. Child Dev. 56(6),1479-1498.

McClure, E.B., 2000. A meta-analytic review of sex differences in facial expression processing and their development in infants, children, and adolescents. Psychol. Bull. 126, 424-453.

Mueser, K., Doonan, R., Penn, D., Blanchard, J., Bellack, A., Nishith, P., DeLeon, J., 1996. Emotion recognition and social competence in chronic schizophrenia. J. of Abnormal Psychology 105, 271-275.

Mueser, K., Bellack, A., Douglas, M., Wade, J., 1991. Prediction of social skill acquisition in schizophrenic and major affective disorder patients from memory and symptomatology. Psychiatry Res. 37, 281-296.

Nelson, H.E., Willison, J., 1982. National Adult Reading Test (NART), Second Edition.

Nestor, P.G., Han, S.D., Niznikiewicz, M., Salisbury, D., Spencer, K., Shenton, M.E. & McCarley, R.W., 2001. Semantic disturbance in schizophrenia and its relationship to the cognitive neuroscience of attention. Biol. Psychology 57(1-3), 23-46.

Penn, D., Spaulding, W., Reed, D., Sullivan, M., 1996. The relationship of social cognition to ward behaviour in chronic schizophrenia. Schizophr. Res. 20, 327-335.

Poole, J.H., Tobias, F., Vinogradow S., 2000. The functional relevance of affect recognition errors in schizophrenia. J. of the Int. Neuropsychol. Soc. 6, 649-658.

Rahman, Q., Abrahams, S., Jussab, F., 2005. Sex differences in a human analogue of the Radial Arm Maze: the “17-Box Maze Test”. Brain Cogn. 58(3), 312-317.

Raven, J.C., Court, J.H., Raven, J., 1996. Standard progressive matrices: with adult US norms. Ed. (SPM) - Oxford: Oxford Psychologists; London: Lewis & Co.

Roberts, J.E., Bell, M.A., 2003. Two- and three-dimensional mental rotation tasks lead to different parietal laterality for men and women. Int. J. of Psychophysiology 50(3), 235-246.

Ross, E.D., Orbelo, D.M., Cartwright, J., Hansel, S., Burgard, M., Testa, J.A., Buck, R., 2001. Affective-prosodic deficits in schizophrenia: comparison to patients with brain damage and relation to schizophrenic symptoms [corrected]. J. of Neurology, Neurosurgery and Psychiatry 70, 597-604. Erratum in: 2001, J. of Neurology, Neurosurgery and Psychiatry 71, 283.

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Schmand, B., Lindeboom, J., Harskamp, F. van., 1992. NLV: Nederlandse leestest voor volwassenen: handleiding (NLV) / Lisse : Swets & Zeitlinger.

Scholten, M., Aleman, A., Montagne, B., Kahn R., 2005. Schizophrenia and processing of facial emotions: sex matters. Schizophr. Res. 78, 61-67.

Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59, 22-33.

Silver, H., Feldman, P., Bilker, W., Gur, R.C., 2003. Working memory deficit as a core neuropsychological dysfunction in schizophrenia. Am. J. Psychiatry 160, 1809-1816.

Speck, O., Ernst, T., Braun, J., Koch, C., Miller, E., Chang, L., 2000. Gender differences in the functional organization of the brain for working memory. Neuroreport 3;11(11), 2581-2585.

Spohn, H.E., Strauss, M.E., 1989. Relation of neuroleptic and anticholinergic medication to cognitive functions in schizophrenia. J. Abnorm. Psychol. 98(4), 367-380.

Walder, D., Seidman, L., Cullen, N., Su, J., Tsuang, M., Goldstein J., 2006. Sex differences in language dysfunction in schizophrenia. Am. J. Psychiatry 163, 470-477.

Zanello, A., Perrig, L., Huguelet, P., 2006. Cognitive functions related to interpersonal problem-solving skills in schizophrenic patients compared with healthy subjects. Psychiatry Res. 30;142(1), 67-78.

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Behavioral Inhibition System (BIS), Behavioral Activation System (BAS) and schizophrenia:

relationship with psychopathology and physiology.

Marion R.M. ScholtenJack van HonkAndré AlemanRené S. Kahn

Journal of Psychiatric Research, 2006;40:638-645.

4Behavioral Inhibition and Activation

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AbstractObjective: The Behavioral Inhibition System (BIS) and the Behavioral Activation System (BAS) have been conceptualized as two neural motivational systems that regulate sensitivity to punishment (BIS) and reward (BAS). Imbalance in BIS and BAS levels has been reported to be related to various forms of psychopathology. Since sensitivity to stress has been supposed to be a pathway for the development of psychotic symptoms, the aim of this study is to examine BIS and BAS scores in schizophrenia and their relationship with psychopathology and physiology. Method: 42 patients with schizophrenia (26 men,16 women), stable on atypical antipsychotics, and 37 healthy controls (17 men, 20 women) were assessed with the use of the Behavioral Inhibition and Behavioral Activation scales. Since in-creased average heart rate (HR) and decreased heart rate variability (HRV) have been reported in patients with schizophrenia and have been shown to correlate with inhibited behaviour, these psychophysiological measures were also obtained.The BIS/BAS data and HR/HRV data were both analyzed by a (M)ANOVA. Corre-lation coefficients were computed for associations between BIS/BAS data, HR/HRV data, and patient variables.Results: On the BIS, patients showed higher sensitivity to threat than control sub-jects. Higher BIS sensitivity correlated with longer duration of illness, and lower negative symptoms on the PANSS. The BAS scores did not reveal differences be-tween patients and controls. In patients, low BAS sensitivity correlated with low dosage of medication. On the physiological measures patients showed a signifi-cantly higher HR and lower HRV compared to controls, which was limited to cloz-apine treated patients. No correlations were found between HR/HRV scores and BIS/ BAS scores or patient variables. Conclusions: Male as well as female patients with schizophrenia are more sen-sitive to threat than healthy controls. This may reflect a trait-related characteris-tic, and is not reflected in state-related psychophysiological measures.

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1. Introduction Gray (1976, 1987, 1994) conceptualized two neural motivational systems that regulate the intensity of approach and withdrawal behaviour in response to en-vironmental stimuli: the Behavioral Activation System (BAS) and the Behavioral Inhibition System (BIS). BAS is hypothesized to control approach behaviour in response to cues of reward via dopaminergic activity in the mesolimbic system (Depue & Collins, 1999; Gray, 1994), whereas BIS is hypothesized to be sen-sitive to cues of threat and punishment and to activate responses of inhibition and avoidance via noradrenergic and serotonergic activity in the septohippocam-pal system (Depue & Iacono, 1989; Gray, 1982, 1994). Recently, Gray’s theory has been adapted, viewing the BIS being distributed among a number of neural structures controlled by the septo-hippocampal system and the amygdala and re-garding the BIS as sensitivity to conflicts in general (Gray & McNaughton 2000; McNaughton & Corr 2004).

Sensitivity of the BIS/BAS systems is biologically based, while reactivity of the systems is conditioned by environmental input. Therefore, individual differenc-es in risk factors and protective factors (e.g. gender differences in socialization with respect to reward and punishment conditioning) will affect the sensitivity to punishment and reward. Gray’s theory is one of the most influential biologically based personality theories, and has motivated research in the neurophysiolog-ical (e.g. Blair, 2003; Coan & Allen, 2003; Cools et al., 2005; Hawk & Kowmas, 2003; Keltinkangas-Järvinen et al., 1999; Reuter et al., 2005; Sutton & David-son, 1997), and the molecular genetic basis of the BIS and BAS systems (Cools et al., 2005). For instance, this research has shown that BIS scores predict ser-otonergic modulation of amygdala responses to fearful faces (Cools et al. 2005) and that the interaction of COMT and DRD2 polymorphisms predicts variations in the behavioral approach system (Reuter et al. 2005).

Although there have been previous attempts to measure Gray’s BIS/BAS dimen-sions, these have all been hampered by considerable conceptual and psychomet-ric problems. Therefore Carver and White (1994) developed a brief questionnaire to measure BIS and BAS sensitivities, focussing mainly on the emotional conse-quences of BIS/BAS sensitivity. The BIS items assess responsiveness to impend-ing punishing events and the BAS items asess responsiveness to reward (BASR), funseeking (BASF), and drive towards appetitive goals (BASD) in 3 sub-scales. The Carver and White scales are the most comprehensive and specific measure of BIS/BAS sensitivities. Several validation studies found support for the validity of this BIS/BAS scales (Campbell-Sills et al., 2004; Heubeck et al., 1998; Jorm et al., 1999), and showed the generalizability across samples (n=646) from the USA, UK and Italy (Leone et al., 2001). In clinical studies (Carver et al., 2000; Kasch et al., 2002) BIS/BAS levels, assessed with this questionnaire, proved to be stable over time and clinical state, being more a measure of trait (correlating with measures of personality constructs) than of state (correlating with meas-ures of current clinical symptoms).

Sex differences have been reported for the BIS/BAS scales, with women show-ing higher sensitivity on the BIS (Leone et al., 2001). Externalizing disorders,

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including substance abuse and antisocial behaviour, are more frequent in men (Rosenfield, 2000), and have been found to be significantly associated with high-er BAS scores (Newman et al., 1997, 2005).

Overactivity and underactivity in the BIS and BAS systems, and relative im-balance between BIS and BAS systems, have been related to risk for various forms of psychopathology (Johnson et al., 2003). For example, depression has been shown to be associated with high sensitivity on the BIS and low sensitivity on the BAS (Kasch et al., 2002), bipolar disorder with both elevated BIS and BAS (Depue & Iacono, 1989; Johnson et al., 2000; Meyer et al., 2001), anxiety disor-der (Carver, 2004), nervousness and high levels of internalizing behaviour (Colder & O’Connor 2004) with high BIS sensitivity, and Attention Deficit Hyperactivity Disorder (ADHD) with low BIS sensitivity (Matthys et al., 1998). Higher sensitiv-ity to reward (BAS) has been suggested to underlie psychopathy, and high lev-els of externalizing problems (Newman et al., 1997, 2005). Surprisingly, to date, the BIS/ BAS scales have not been investigated in patients with schizophrenia. However, in a study by Berenbaum and Fujita (1994) patients with schizophre-nia have been found to show increased neuroticism and decreased extraversion compared to controls. Therefore, we hypothesized patients to show higher sen-sitivity to punishment (BIS) than control subjects.

Excessive phasic dopaminergic transmission has been suggested to underlie psychotic (positive) symptoms and increased emotional reactivity in schizophre-nia (Aleman & Kahn, 2005; Davis et al. 1991). Since the mesolimbic system is involved in behavioral reinforcement and motivation, and since the role of the dopaminergic reward system is to direct attention towards reward-indicating stimuli and to predict reward, excessive dopaminergic transmission may result in over-attribution of meaning to otherwise irrelevant cues. Reduced dopamine receptor sensitivity in the striatum, increased by neuroleptics, is associated with negative symptoms (avolition, apathy, affective flattening) (Heinz et al., 1998) and may reduce motivational and emotional responses to reward-indicating sit-uations. (Robbins & Everitt, 1996; Schultz et al., 1997). Therefore we expected higher sensitivity to reward (BAS) to correspond to high levels of positive symp-toms, and lower sensitivity to reward to high levels of negative symptoms.

With regard to sex differences, a recent study by Myin-Germeys et al. (2004) indicated that women with psychotic symptoms reacted more strongly to daily life stress than men, with increase in negative affect and decrease in positive affect. Since women have been found to show higher sensitivity on the BIS (Jorm, 1999, Leone, 2001), and more internalizing problems than men (Rosenfield, 2000), we also expected women with schizophrenia to be more sensitive to threat (i.e., el-evated BIS scores) than men with schizophrenia.

Several studies have reported increased average heart rate (HR) (Rechlin et al., 1994; 1995; Zahn et al., 1981a, 1981b,1997) and decreased heart rate variability (HRV) (Bär et al., 2005), in patients with schizophrenia. Since increased HR and decreased HRV have been shown to correlate with inhibited behaviour (Kagan et al., 1987, 1988; Reznick et al., 1986) these psychophysiological measures were

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also obtained. We expected high BIS sensitivity to correlate with high scores on average heart rate (HR), and with low scores on heart rate variability (HRV).

2. Method 2.1. ParticipantsForty-two patients with schizophrenia (26 men, 16 women) and 37 healthy con-trols (17 men, 20 women) participated in this study.

All patients were recruited from the Schizophrenia Research Unit of the Utrecht University Hospital. Most patients (n=40) were outpatients. Some of them had been hospitalized for a first psychosis or a relapse for several weeks, others vis-ited the clinic for a second opinion or received treatment on an outpatient ba-sis for several months. Psychiatric diagnosis was established by an independent trained psychiatrist via a structured interview the Comprehensive Assessment of Symptoms and History (CASH). The CASH is a commonly used diagnostic inter-view schedule, specifically developed to measure current and past psychotic and affective symptoms (Andreasen, 1992).

To avoid effects of affective symptoms and co-medication on the BIS/BAS sen-sitivities or physiological measures, only patients with a diagnosis of schizophre-nia without prominent affective symptoms (e.g. no schizo-affective disorder, no concurrent depression) and no other concomitant axis I disorder were recruited for the study. Furthermore, all patients had to be on atypical antipsychotics with-out co-medication, such as tranquillisers or antidepressants, at the time of test-ing. Patients were studied while clinically stable (at least 6 weeks stable on the same dosage of atypical antipsychotics, without any relapse). Positive and nega-tive symptoms were measured using the Positive And Negative Syndrome Scale (PANSS; Kay et al., 1987), at the day of testing. This rating scale was developed from the BPRS and the Psychopathology Rating Scale and is widely used in re-search. The PANSS evaluates three categories of symptoms in schizophrenia (7 positive symptoms, 7 negative symptoms and 16 symptoms of general psychopa-thology) on a 7-point scale (1=absent; 7=extreme). The total score of the PANSS ranges from 30-210, with higher scores indicating more pronounced symptoms. Ratings also concern the previous week.

Most female (n=14) and male (n=22) patients had been diagnosed with schiz-ophrenia, paranoid subtype. Only 1 female patient and 3 male patients had been diagnosed with a disorganized subtype, 1 male and 1 female patient with an undif-ferentiated subtype. Male and female patients did not differ in age at first psycho-sis, number of hospitalisations, duration of illness and dosage of medication.

The control subjects were volunteers from the Utrecht University Hospital or were recruited through an advertisement in local newspapers. They were screened (using the Mini-International Neuropsychiatric Interview Plus (MINI-Plus), for current or past psychiatric illness (in themselves or first-degree relatives). The M.I.N.I., developed by Sheehan and Lecrubier (1998), is a short, structured di-agnostic interview for DSM-IV and ICD-10 psychiatric disorders. The M.I.N.I. has been validated against the (SCID-P), the ICD-10 (CIDI) and against expert

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88 Behavioral Inhibition and Activation

opinion in a large sample in four European countries. Controls had to be free of medication.

Exclusion criteria for both groups (screened with a medical history question-naire and interview) included: head injury with documented cognitive sequelae or loss of consciousness longer than 5 minutes; medical illness or neurological disorder associated with neurocognitive impairment; any history of cardiac, he-patic, renal, pulmonary or endocrine disorder; and an active substance use dis-order diagnosis in the 6 weeks prior to study.

To avoid effect of the menstrual cycle, all female participants were tested in the first 10 days of their cycle (starting from day 1 of menstruation).

Patients and control subjects did not differ significantly in terms of age, edu-cation and socio-economic status of the parents, but differed significantly in liv-ing with their parents (more often in patients) or living with a partner or friends (more often in controls).

Group characteristics of patients and controls are reported in Table 1. After complete description of the study to the subjects, written informed con-

sent was obtained. The Medical Ethics Committee of the University Medical Cen-tre Utrecht approved the study.

2.2. Procedure2.2.1. BIS BAS scalesSubjects were presented the Dutch version (Putman et al., 2004) of th BIS BAS scales, a 20-item self-rating questionnaire with good psychometric properties (Carver & White, 1994; Campbell-Sills et al., 2004; Jorm et al., 1999). The ques-tionnaire comprises 7 BIS items and 13 BAS items. Each item has 4 response op-tions ranging from 1 (strongly agree) to 4 (strongly disagree). To avoid a problem of multiple comparisons, we did not use the 3 subscales of the BAS (responsive-ness to reward: BASR; funseeking: BASF; and drive towards appetitive goals: BASD).

2.2.2. Physiological MeasuresPhysiological measures were recorded during four minutes of rest, before assess-ment of questionnaires. Participants were asked to refrain from eating, caffeine drinks, smoking and physical exercise during one hour before the assessment. Heart rate was recorded via three electrodes on the breast (over the jugular notch of the sternum, between the collar bones; under the left breast, 4 cm under the nipple, between two ribs; at the right lateral side, between the two lower ribs). Measurements were acquired using the Ambulatory Monitoring System (VU-Am-sterdam), which calculates Inter-Beat Interval (IBI) time series online.

Physiological measures, BIS/BAS scales and PANSS were assessed at the same day.

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Table 1. Characteristics of all participants

Characteristic Male patients(N=26)

Female Patients(N=16)

Male controls(N=17)

Female controls(N=20)

Mean SD Mean SD Mean SD Mean SD

Age (years) 27.5(Range 19-45y)

6.9 28.1(Range19-41y)

6.5 28.0(Range20-41y)

5.3 28.7(Range20-44y)

5.3

Subjects’ education (1)

2.65 1.09 3.13 0.81 2.94 0.97 3.15 0.88

PANSS Positive Syndrome scale scores(2)

11.35 3.55 11.81 4.62

PANSS Negative syndrome scale scores(2)

15.46 4.64 15.06 5.30

PANSS General symptom scores(2)

24.62 4.25 26.62 8.98

Duration of illness (years) (2)

4.29 3.37 5.16 4.87

Age at first psychosis(2)

23.23 5.76 22.94 4.88

Number of hospitalizations(2)

1.65 1.35 2.12 1.54

Dose of atypical antipsychotics(2,3)

14.43 6.53 12.34 5.40

(1) Education was measured on a 4-point scale: low (1); middle (2); high (3); university (4)(2) Differences between male and female patients were non-significant(3) Dose of atypical antipsychotics in mg olanzapine equivalents (Dose conversion: 20

mg of olanzapine is equivalent to 6 mg of risperidone, 700 mg of quetiapine or 500 mg of clozapine; ref.: Kohler, 2003) Olanzapine (N=14; range = 10–25 mg; mean dose 16 mg) Clozapine (N=16; range = 75–750 mg; mean dose 320 mg = 13 mg equivalent olan-zapine) Risperidone (N=8; range = 1–8 mg; mean dose 3.8 mg = 12 mg equivalent olanzap-ine) Quetiapine (N= 4; range = 400–400 mg; mean dose 400 mg = 11 mg equivalent olanzapine)

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2.3. Statistical analysisThe BIS and BAS data were both analyzed by a 2x2 ANOVA (Sex and Group) and the HR/HRV data by a MANOVA in SPSS. Since BAS scores have been found to be higher in men (Jorm et al., 1999), and BIS scores have been found to be higher in women (Leone et al., 2001), gender was controlled in both the corre-lations with BIS and BAS.

The unequal distribution of males and females in the two groups was also tak-en into account by introducing gender as a factor into the ANOVA.

On the BIS/BAS measures, analyses of co-variance were conducted with du-ration of illness and age as co-variates. On the physiological data an analysis of co-variance was conducted with clozapine as a co-variate.

Correlation coefficients (Pearson) were computed for associations between BIS/BAS data, HR/HRV data, and patient variables (duration of illness, dosage of medication). For correlations between rating scales (BIS/BAS, PANSS), nonpara-metric correlation coefficients (Spearman’s r) were computed.

3. Results3.1. Clinical variablesAs can be seen in Table 1, no significant differences were found in the patient groups between men and women in severity of negative symptoms, positive symp-toms and general psychopathology sub-scale, measured by the PANSS.

3.2. BIS / BAS scores3.2.1. BISA 2×2 ANOVA (Group, Sex) on all BIS items revealed a significant effect of Group (F(df 1,75) = 4.7; p = .034), controls showing less sensitivity than patients, and of Sex (F(df 1,75) = 5.1; p = .026), men showing less sensitivity than women. There was no interaction.

No correlations were found between BIS scores and positive, general or total scores on the PANSS, dosage of medication or type of medication. Lower sensi-tivity on the BIS correlated with higher negative symptoms on the PANSS (r = -314; p= .043). Higher sensitivity on the BIS correlated with longer duration of illness (r = .337; p = .029) and higher age (r = .395; p = .010). Therefore we conducted separate analyses on the BIS with duration of illness and age as co-variates. The main effect of Sex was nonsignificant, when duration of illness was entered as a covariate (duration of illness: F (df 1,39) = 4.8; p = .035; Sex: F (df 1,39) = .16; p = .691); age as a covariate had no effect.

3.2.2. BASA 2×2 ANOVA (Group, Sex) on all BAS items combined, did not show any signif-icant effects. No correlation was found between BAS scores and duration of ill-ness or positive / negative scores on the PANSS. High BAS-sensitivity correlated with high dosage of current medication (r = .372; p = .015).

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The results also showed positive correlations between dosage of medication and positive symptoms (r = .350; p = .023), general symptoms (r = .325; p = .036) and total symptoms (r = .363; p = .018) on the PANSS, and a negative correlation between dosage of medication and level of education (r = -.331; p = .033).

3.3. Physiology Average heart rate (HR) and heart rate variability (HRV) were calculated for base-line periods. For HRV, we used the root mean squares of successive differences (R-MSSD), which is a reliable indicator of parasympathetic control of the heart (De Geus, Willemsen, Klaver, & Van Doornen, 1995).

A MANOVA with both physiological measures as dependent variables and Group and Sex as independent variables showed a significant difference between pa-tients and controls (F (df 2,74) = 6.5 ; p = .003), but not between men and wom-en. A post hoc analysis showed that this difference between patients and controls was significant in both HR (F (df 1,75) = 11.9; p = .001) and in HRV (F (df 1,75) = 8.9; p = .004), with higher HR and lower HRV in patients. In addition, a sig-nificant interaction between Group and Sex was observed in the MANOVA (F (df 2,74) = 3.2; p = .046). Post-hoc tests revealed that this was specific for the HR (F (df 1,75) = 5.1; p = .026), with lower HR in female patients than in male pa-tients and higher HR in female controls compared to male controls.

Since clozapine-treated patients have been reported to show markedly increased HR and decreased HRV compared to patients using other neuroleptic medication (Cohen et al., 2001), we conducted a separate analysis with clozapine use as a covariate. This reduced the main effect of Group to a nonsignificant trend for HRV, F(df 1,76) = 2.2; p = .099. The effect of clozapine on HRV was F(df 1,76) = 7.7; p = .007. For HR, the main effect of Group was also nonsignificant, when cloza-pine was entered as a covariate, F(df 1,76) = 1.8; p = .184. The effect of cloza-pine on HR was highly significant, F(df 1,76) = 24.0; p < .0005.

No correlations were found between HR/HRV scores and BIS/ BAS scores, PANSS scores, duration of illness, or dosage of medication.

The results of all subjects on the BIS/BAS questionnaire and physiological measures are listed in Table 2 and 3.

4. Discussion This study examined sensitivity to punishment (BIS) and reward (BAS) in pa-tients with schizophrenia compared to controls. In addition, we analyzed psy-chophysiological measures of average heart rate (HR) and heart rate variability (HRV) in both groups.

Patients showed a higher sensitivity to threat than controls. This higher BIS sensitivity correlated with longer duration of illness and lower scores on the neg-ative PANSS symptoms. Higher BIS sensitivity has also been reported in anxiety disorder, depression and bipolar disorder. However, the results in our study can-

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Table 2. Headline Scores BIS BAS and physiology of all participants

Characteristic Male patients (N=26)

Female patients(N=16)

Male controls(N=17)

Female controls(N=20)

Mean SD Mean SD Mean SD Mean SDBIS(1) 14.54 3.29 13.81 4.37 17.41 3.54 14.45 3.17BAS(1) 23.92 5.55 25.44 4.82 24.53 4.30 24.15 3.60

(N=26) all atypical antipsychotics

(N=16) all atypical antipsychotics

HRA 90.11 18.48 81.80 14.58 71.16 8.59 77.89 12.17

HRV 20.51 21.36 29.27 20.37 40.30 18.89 43.83 35.70

(N=11) clozapine

(N=5) clozapine

HRA 103.21 14.13 91.17 18.15

HRV 9.07 7.48 14.38 13.49

(N=15) olanzapine, quetiapine, risperidone(2)

(N=11) olanzapine, quetiapine, risperidone(2)

HRA 80.50 15.28 77.55 11.11

HRV 28.91 24.42 36.03 19.70

(1) low scores on the BIS or BAS correspond with high sensitivity on the BIS or BAS(2) risperidone (male patients: n=5; female patients: n=3), olanzapine (male patients: n=8; female patients: n= 6), quetiapine (male patients: n=2; female patients: n=2)

not be attributed to a co-morbid affective disorder or anxiety disorder, since none of the patients met criteria for these disorders at the time of testing and none of them used antidepressants or anxiolytic medication. In addition, patients with a schizo-affective disorder were not included.

Scores on the psychophysiological measures showed a higher average heart rate (HR) and lower heart rate variability (HRV) in patients, indicating reduced parasympathetic activity (Toichi et al., 1997; Malaspina et al., 2002) and high-

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Table 3: Overview ANOVA’s

N = 79 df F pBIS Group 1,75 4.7 .034BIS Sex 1,75 5.1 .026BIS Group x Sex 1,75 1.9 .174

With duration of illness as covariate:Duration of illness 1,39 4.8 .035BIS Sex 1,39 .16 .691

BAS Group 1,75 .100 .753BAS Sex 1,75 .28 .600BAS Group x Sex 1,75 .77 .382

HR Group 1,75 11.9 .001HR Sex 1,75 .06 .813HR Group x Sex 1,75 5.1 .026

HRV Group 1,75 8.9 .004HRV Sex 1,75 1.1 .290HRV Group x Sex 1,75 .20 .652

With clozapine as covariate:clozapine 1,76 24.0 < .0005HR Group 1,76 1.8 .184

clozapine 1,76 7.7 .007HRV Group 1,76 2.2 .099

HR = average Heart RateHRV = Heart Rate Variability

er autonomic arousal (Zahn et al., 1981a, 1981b, 1997). Although increased HR and decreased HRV have been reported in unmedicated patients (Bär et al., 2005), in our sample further analyses showed that this finding was limited to pa-tients treated with clozapine. This is in line with a study by Rechlin (1995) which reported no differences in HRV parameters between patients with schizophrenia and control subjects, and with several studies (Agelink et al., 2001; Cohen et al., 2001; Eschweiler et al., 2002), showing significantly higher heart rate and lower

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heart rate variability in clozapine-treated patients compared to control subjects or compared to patients using olanzapine. This can be explained by the high an-ticholinergic properties of clozapine.

No correlations have been found between psychophysiological measures and dosage of medication.

Our hypothesis that high BIS sensitivy would correlate with the cardiac meas-ures (increased HR and decreased HRV) was not confirmed, since no correlations between BIS/BAS scores and HR/HRV scores have been found. Results from a study by Dishman et al., (2000) in healthy men and women, suggested that re-cent experience of emotional stress, but not trait anxiety, influenced HRV meas-ures. Carver and White (1994) also have asserted that the BIS scale is not strongly related to state anxiety measures, since it primarily reflects a trait characteristic, i.e. sensitivity towards stress, rather than the way anxiety is experienced. This could also explain why Bär et al. (2005) did find increased HR and decreased HRV in acute schizophrenic patients, not receiving medication for at least 8 weeks, as these patients had high levels of psychopathology at the time of testing. The re-sults on the BIS scale confirmed our hypothesis that patients with schizophrenia show increased sensitivity to cues of threat and non-reward. However, it remains unclear whether the high sensitivity to threat on the BIS in patients may be the result of having been psychotic, a predisposition towards psychoses, or perhaps both. Future research should employ longitudinal measurements in order to dis-entangle cause-and-effect relationships.

Dispositional responsiveness to threat may cause a bias toward identification of emotional stimuli as negative and may result in impaired regulation of social behaviour. In addition, misinterpretation of emotional information as threaten-ing may be an important vulnerability factor to psychosis. A study by Gable et al. (2000) in healthy participants also showed that high BIS sensitivity amplified affec-tive reactions to negative events. These findings are in line with a study on emo-tional reactivity to daily life stress, in patients with different psychotic disorders, measured with an experience sampling method (Myin-Germeys et al., 2001). In this study, patients showed an increase in negative affect and a decrease in pos-itive affect in reaction to daily life stress, while their first-degree relatives showed the same increase in negative affect, but a decrease in positive affect, intermedi-ate to that of patients and controls. Therefore the authors suggested that higher levels of emotional reactivity to external stimuli, and misinterpretation of emo-tional information as threatening might be associated with higher levels of (famil-ial) risk for psychosis. Since sensitivity to punishment has also been found to be increased in patients with anxiety and mood disorders, there may be an area of shared vulnerability between affective and psychotic disorders. It is important to note that, whereas Myin-Germeys investigated self-reports of actual daily-life ex-periences, we investigated a more trait-like motivational disposition. Results from a study in patients with different psychotic disorders (Leone et al., 2001), sug-gested that women show increased negative affect in reaction to daily life stress compared to men. However, in our study, male as well as female patients showed higher BIS sensitivity compared to healthy controls of their own sex.

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BAS scores were expected to vary with the positive (high BAS) and negative symptoms (low BAS) on the PANSS. However, no differences were found in sensi-tivity to reward (BAS) between patients and controls and between men and wom-en. Since all patients had been treated with atypical antipsychotic medications, and the BAS is supposed to control reward sensitivity via dopaminergic activity, medication may have influenced the results. Indeed, a correlation between BAS-sensitivity and dosage of medication was found, implying that patients with high-er BAS sensitivity also were treated with a higher dosage of medication.

In conclusion, the results of the present study demonstrated that male and female patients with schizophrenia are more sensitive to punishment than con-trol subjects and are more likely to regard stimuli as threatening. This may im-ply that schizophrenia is characterized by a vulnerability to anxiety, which may in turn be a pathway to psychosis. Dysregulation and imbalance of motivational systems in schizophrenia may have clinical implications for treatment and relapse prevention. For example, a tendency to misinterpretation of emotional informa-tion in the basis of BIS/BAS sensitivities in patients, might benefit from cognitive-behavioral therapy, stress-management, or treatment with Selective Serotonine Reuptake Inhibitors (SSRI’s).

A limitation of this study is that we only included patients and healthy con-trols, and no relatives of patients or controls at high risk. A future study involv-ing relatives of patients with schizophrenia may reveal if sensitivity to threat is a risk factor in this group. Furthermore, the sample is a ‘selective sample’ with regard to medication (only atypical antipsychotics, no co-medication, no medi-cation-free or medication-naive patients) and psychopathology (no patients with prominent comorbid affective symptoms, recent drug abuse, or a history of vio-lent behaviour). Especially on the BAS scores one might expect higher sensitiv-ities in medication-free patients with psychotic symptoms or manic symptoms, and in psychotic patients with antisocial tendencies. Future studies may shed light on this issue.

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5. ReferencesAgelink MW, Majewski T, Wurthmann C, Lukas K, Ullrich H, Linka T, Klieser E. Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine. J Clin Psychopharmacol. 2001;21(1):8-13.

Aleman A & Kahn RS. Strange feelings: Do amygdala abnormalities dysregulate the emotional brain in schizophrenia? Prog Neurobiol. 2005 Dec;77(5):283-298. Epub 2005 Dec 13.

Andreasen NC, Flaum M, Arndt S. The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 1992;49:615-623.

Bär KJ, Letzsch A, Jochum T, Wagner G, Greiner W, Sauer H. Loss of efferent vagal activity in acute schizophrenia. J Psychiatr Res. 2005;39(5):519-527.

Berenbaum H, Fujita F. Schizophrenia and personality: exploring the boundaries and connections between vulnerability and outcome. J Abnorm Psychol 1994;103(1):148-158.

Blair C. Behavioral Inhibition and behavioral activation in young children: Relations with self-regulation and adaptation to preschool in children attending head start. Dev Psychobiol 2003;42:301-311.

Campbell-Sills L, Liverant GI, Brown TA. Psychometric evaluation of the behavioral inhibition/behavioral activation scales in a large sample of outpatients with anxiety and mood disorders. Psychol Assess 2004; 16(3):244-254.

Carver CS & White TL. Behavioural Inhibition, Behavioural Activation, and Affective responses to Impending Reward and Punishment: The BIS/BAS scales. 1994;67:319-333.

Carver CS, Sutton SK, Scheier MF. Action, emotion and personality: emerging conceptual integration. Personality and Social Psychology Bulletin 2000;26:741-751.

Carver CS. Negative affects deriving from the behavioral approach system. Emotion 2004;4(1):3-22.

Coan JA, Allen JJB. Frontal EEG asymmetry and the behavioral activation and inhibition systems. Psychophysiology 2003;40:106-114.

Cohen H, Loewenthal U, Matar M, Kotler M. Association of autonomic dysfunction and clozapine. Heart rate variability and risk for sudden death in patients with schizophrenia on long-term psychotropic medication. Br J Psychiatry. 2001;179:167-171.

Page 97: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter four 97

Colder CR, O’Connor RM. Gray’s reinforcement sensitivity model and child psychopathology: laboratory and questionnaire assessment of the BAS and BIS. J Abnorm Child Psychol. 2004;32(4):435-451.

Cools R, Calder AJ, Lawrence AD, Clark L, Bullmore E, Robbins TW. Individual differences in threat sensitivity predict serotonergic modulation of amygdala response to fearful faces. Psychopharmacology (Berl). 2005;180(4):670-679.

Davis KL, Kahn RS, Ko G, Davidson M. Dopmaine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991;148:1474-1486.

Depue RA & Collins PF. Neurobiology of the structure of personality: Dopamine, facilitation of incentive motivation, and extraversion. Behavioral and Brain Sciences. 1999;22:491-569.

Depue RA & Jacono WG. Neurobehavioral aspects of affective disorders. Annual Review of Psychology 1989;40:457-492.

Dishman RK, Nakamura Y, Garcia ME, Thompson RW, Dunn AL, Blair SN. Heart rate variability, trait anxiety, and perceived stress among physically fit men and women. Int J Psychophysiol. 2000;37(2):121-133.

Eschweiler GW, Bartels M, Langle G, Wild B, Gaertner I, Nickola M. Heart-rate variability (HRV) in the ECG trace of routine EEGs: fast monitoring for the anticholinergic effects of clozapine and olanzapine? Pharmacopsychiatry. 2002;35(3):96-100.

Gable SL, Reis HT, Elliot AJ. Behavioral activation and inhibition in everyday life. J Pers Soc Psychol 2000;78:1135-1149.

Geus de, EJ, Willemsen, GH, Klaver, CH, Van Doornen, LJ. Ambulatory measurement of respiratory sinus arrhythmia and respiration rate. Biological Psychology. 1995;41(3):205-227.

Gray JA. The behavioural inhibition system: A possible substrate for anxiety. In: Feldman MP, Broadhurst A, eds. Theoretical and experimental bases of the behaviour therapies, London:Wiley; 1976:3-41.

Gray JA. The neuropsychology of anxiety: An inquiry into the functions of the septohippocampal system. New York: Oxford University Press; 1982.

Gray JA. The neuropsychology of emotion and personality. In: Stahl SM, Iversen SD, Goodman EC, eds. Cognitive Neurochemistry. Oxford University Press, Oxford, UK;1987:171-190.

Page 98: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

98 Behavioral Inhibition and Activation

Gray JA. Three fundamental emotion systems. In: Ekman P, Davidson RJ, eds. The nature of emotion: Fundamental questions, New York: Oxford University Press;1994:243-247.

Gray JA, McNaughton N. The neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system, 2nd ed. Oxford: Oxford University Press, 2000.

Hawk LW, Kowmas AD. Affective modulation and prepulse inhibition of startle among undergraduates high and low in behavioral inhibition and approach. Psychophysiology 2003;40:131-138.

Heinz A, Knable MB, Coppola R, Gorey JG, Jones DW, Lee KS et al. Psychomotor slowing, negative symptoms and dopamine receptor availability- an IBZM study in neuroleptic-treated and drug-free schizophrenic patients. Schizophr Res 1998;31:19-26.

Heubeck BG, Wilkinson RB, Cologon J. A second look at Carver and White’s (1994) BIS/BAS scales. Personality and IndividualDifferences 1998;25:785-800.

Johnson SL, Sandrow D, Meyer B et al. Increases in manic symptoms after life events involving goal attainment. J Abnorm Psychol 2000;109(4):721-727.

Johnson SL, Turner RJ, Iwata N. BIS/BAS kevels and psychiatric disorder: An epidemiological study. J of Psychopathology and Behavioral Assessment 2003;25(1):25-36.

Jorm AF, Christensen H, Henderson AS, Jacomb PA, Korten AE, Rodgers B. Using the BIS/BAS scales to measure behavioural activation: Factor structure, validity and norms in a large community sample. Personality & Individual Differences 1999;26:49-58.

Kagan J, Reznick JS, Snidman N, Gibbons J, Johnson MO. Childhood derivatives of inhibition and lack of inhibition to the unfamiliar. Child Dev. 1988;59(6):1580-1589.

Kagan J, Reznick JS, Snidman N. The physiology and psychology of behavioral inhibition in children. Child Dev. 1987;58(6):1459-1473.

Kasch KL, Rottenberg J, Arnow BA, Gotlib IH. Behavioral activation and inhibition systems and the severity and course of depression. J Abnorm Psychol 2002;111(4):589-597.

Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale (PANSS). MultiHealth Systems Inc. North Tonawanda, NY. 1987.

Keltinkangas-Järvinen L, Kettunen J, Ravaja N, Näätänen P. Int J of Psychophysiology 1999;33:185-196.

Page 99: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter four 99

Leone L, Perugini M, Bagozzi RP, Pierro A, Mannetti L. Construct validity and generalizability of the Carver-White Behavioural Inhibition System / Behavioural Activation System Scales. European Journal of Personality 2001;15:373-390.

Malaspina D, Dalack G, Leitman D, Corcoran C, Amador XF, Yale S, Glassman A, Gorman JM. Low heart rate variability is not caused by typical neuroleptics in schizophrenia patients. CNS Spectr. 2002;7(1):53-57.

Matthys W, van Goozen SH, de Vries H, Cohen-Kettenis PT, van Engeland H. The dominance of behavioural activation over behavioural inhibition in conduct disordered boys with or without attention deficit hyperactivity disorder. J Child Psychol Psychiatry 1998;39(5):643-651.

McNaughton N, Corr PJ. A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neuroscience and Behavioral Reviews 2004;28:285-305.

Meyer B, Johnson S, Winters R. Responsiveness to threat and incentive in bipolar disorder: relations of the BIS / BAS scales with symptoms. J of Psychopathology and Behavioural Assessment 2001;23:133-143.

Myin-Germeys I, van Os J, Schwartz JE et al. Emotional reactivity to daily life stress in psychosis. Arch Gen Psychiatry 2001;58(12):1137-1144.

Myin-Germeys I, Krabbendam L, Delespaul PAEG, van Os J. Sex differences in emotional reactivity to daily life stress in psychosis. J Clin Psychiatry 2004;65:805-809.

Newman JP, MacCoon DG, Vaughn LJ, Sadeh N. Validating a distinction between primary and secondary psychopathy with measures of Gray’s BIS and BAS constructs. J Abnorm Psychol. 2005;114(2):319-323.

Newman JP, Wallace JF, Schmitt WA, Arnett PA. Behavioural inhibition system functioning in anxious, impulsive and psychopathic individuals. Personality and Individual Differences 1997;23:583-592.

Putman P, Hermans E, van Honk J. Emotional stroop performance for masked angry faces: it’s BAS, not BIS. Emotion 2004;4(3):305-311.

Rechlin T, Claus D, Weis M. Heart rate variability in schizophrenic patients and changes of autonomic heart rate parameters during treatment with clozapine. Biol Psychiatry. 1994;35(11):888-892.

Rechlin T. Effects of psychopharmacologic therapy on heart rate variation. Nervenarzt.1995 ;66(9):678-685.

Page 100: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

100 Behavioral Inhibition and Activation

Reuter M, Schmitz A, Corr P, Hennig J. Molecular genetics support Gray’s personality theory: the interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system. Int J Neuropsychopharmacol. 2005;13:1-12.

Reznick JS, Kagan J, Snidman N, Gersten M, Baak K, Rodenberg A. Inhibited and uninhibited children: a follow-up study. Child Dev. 1986;57:660-680.

Robbins TW & Everitt BJ. Neurobehavioral mechanisms of reward and motivation. Curr Opinion Neurobiol 1996;6:228-236.

Rosenfield, S. Gender and dimensions of the self: Implications for internalizing and externalizing behavior. In: Frank, E. (ed.), Gender and its effects on psychopathology. American Psychopathological Association Series. American Psychiatric Press, Washington, DC, 2000:23-36.

Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science 1997;275:1593-1599.

Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.):the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59:22-33.

Sutton SK, Davidson RJ. Prefrontal brain asymmetry: A biological substrate of the behavioral approach and behavioral inhibition systems. Psychological Science 1997;8:204-210.

Toichi M, Sugiura T, Murai T, Sengoku A. A new method of assessing cardiac autonomic function and its comparison with spectral analysis and coefficient of variation of R-R interval. J Auton Nerv Syst. 1997;62(1-2):79-84.

Zahn TP, Carpenter WT Jr, McGlashan TH. Autonomic nervous system activity in acute schizophrenia: II. relationships to short-term prognosis and clinical state. Arch Gen Psychiatry. 1981a;38(3):260-266.

Zahn TP, Carpenter WT Jr, McGlashan TH. Autonomic nervous system activity in acute schizophrenia: I. method and comparison with normal controls. Arch Gen Psychiatry. 1981b;38(3):251-258.

Zahn TP, Jacobsen LK, Gordon CT, McKenna K, Frazier JA, Rapoport JL. Autonomic nervous system markers of psychopathology in childhood-onset schizophrenia. Arch Gen Psychiatry. 1997;54(10):904-912.

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Schizophrenia and sex differences in empathizing-systemizing abilities

and appraisal of social interaction

Marion R.M. ScholtenAndré AlemanYolanda van BeekRené S. Kahn

Manuscript submitted for publication

5Empathy and perception

of social interaction

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104 Empathy and perception of social interaction

AbstractObjective: Empathic capacities and adequate appraisal of social interactions are crucial for successful social functioning. This study aimed to investigate wheth-er the well-documented female advantage in empathic capacity and social cog-nition is preserved in schizophrenia. Method: 48 patients with schizophrenia (25m, 23 f), and 48 controls (23 m, 25 f) were assessed with the use of the Empathizing-Systemizing Questionnaires (E-SQ; Baron-Cohen) and an Interpersonal Information in Postures Task (IIPT), con-sisting of 2 series of drawings, depicting a social interaction between 2 characters (A and B). On the IIPT-negative, participants were required to imagine they were person A and to indicate how annoying it would be to person B to talk to A. On the IIPT-positive, participants had to choose, between 2 pairs of drawings, the one in which the contact with A was most enjoyable to B. The E-SQ data and the IIPT data were both analyzed by a 2x2 ANOVA. Correlation coefficients were comput-ed for associations between E-SQ scores, IIPT-scores, and patient variables. Results: On Empathizing, scores were lower in patients than in control subjects, and lower in men than in women. Higher Empathizing scores correlated with lower negative symptoms. Systemizing data did not reveal differences between patients and controls, but men showed significantly higher scores than women across groups. On the IIPT-negative, patients showed lower scores compared to controls, and men showed lower scores than women. Positive correlations were found between IIPT-negative scores and Empathizing scores. On the IIPT-posi-tive, no differences were found between patients and controls.Conclusions: These results imply that the female advantage in empathic skills is preserved in schizophrenia. Patients do not differ from controls in the ability to recognize the most favorable interaction out of two social situations, but less of-ten evaluate a social interaction as annoying for the ‘conversation partner’.

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1. IntroductionNumerous studies suggest that female patients with schizophrenia show a bet-ter course and outcome of the disease than their male counterparts (Goldstein et al., 2000; Leung et al., 2000). There is a dearth of studies that investigate puta-tive variables that may underlie such sex differences. Specifically, social cognition might be a viable candidate. For example, women have been reported to excel in social cognitive abilities (Hall, 1978; 1984; McClure et al., 2000), which are vi-tal to social functioning (Hoffman, 1977), and have been found to be impaired in schizophrenia (Langdon et al., 2006; Moran & Hodgins, 2004). Social cognition is a broad concept including social perception, ‘Theory of Mind’ (ToM) skills, and empathy (see for an overview Pinkham et al., 2003). Social perception is gener-ally divided into affect recognition and social cue perception, which can concern complex social interactions or symbolic representations implicated in social inter-action. ‘Theory of Mind’ skills refer to the ability to represent the mental state of others or to make inferences about another’s intentions and have been report-ed to be a strong predictor of global social functioning (Roncone et al., 2002). They are closely related to the concept of empathy, but do not by definition con-cern feelings. Empathy is the ability to recognize and understand emotions and mental states of other persons and to respond to these with an appropriate af-fect (Blair et al., 2005).

Impairment of social cognition and empathic abilities has been found in neu-rodevelopmental disorders such as schizophrenia (Langdon et al., 2006; Moran & Hodgins, 2004) and autism (Baron-Cohen & Wheelwright, 2004), in patients with acquired brain lesions (Shamay-Tsoory et al., 2003, 2004), and in antisocial personality disorder (Blair, 2005; Soderstrom, 2003). Since women have been reported to excel in empathy (Baron-Cohen, 1997, 2002; Davis, 1994; Happe, 1995), as well as in social cognition (especially emotion recognition) (Hall, 1978; 1984; McClure et al., 2000), and since both skills have been shown to be linked to social functioning (Hoffman, 1977), this could imply that the better course and outcome of schizophrenia in women is in part due to preservation of the female advantage in emotional processing. Indeed, with regard to emotion perception, a previous study has shown that the superior female performance on facial af-fect recognition remains unaffected in patients with schizophrenia, although, as a group, patients perform worse than control subjects (Scholten et al., 2005).

In the present study, we aimed to examine for the first time whether the female advantage in empathic capacity and appraisal of social interaction was preserved in schizophrenia. To assess empathic abilities, use was made of two question-naires developed by Baron-Cohen. Studying impairment in social skills in autism, Baron-Cohen et al. (1999) conceptualized a model with two profiles (‘Empathiz-ing’ and ‘Systemizing’) as major dimensions, and developed two questionnaires (E-S questionnaires) to assess them. Empathizing was defined as ‘the capacity to identify another person’s emotions and thoughts by inferring their mental states and responding to these with an appropriate emotion’, and Systemizing as ‘the capacity to analyze the variables in a system, and to derive the underlying rules that govern the behavior of a system’. Empathizing enables to predict and un-

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106 Empathy and perception of social interaction

derstand behavior and feelings of other persons, systemizing enables to predict and control the behavior of systems. In patients with autism, lower empathizing and higher systemizing abilities were reported compared to controls (Baron-Co-hen, 2002). In order to investigate the appraisal of social interaction, a novel task was developed. Since deficits in language processing and facial affect recognition are both common in patients with schizophrenia, and might influence the test re-sults, this task focussed on processing interpersonal information in postures and did not require recognition of facial emotions.

We predicted patients with schizophrenia to be impaired in empathizing abili-ties and appraisal of social interaction. Furthermore, we expected the advantage in empathic capacity to be preserved in female patients with schizophrenia. In contrast to findings in autistic patients, the scores on systemizing were expected to be equal in patients and controls and the normal sex difference, with higher scores in men, was expected to be preserved. On the social interaction percep-tion task, healthy subjects were predicted to outperform patients and women to outperform men.

2. Method2.1. Participants Forty-eight patients with schizophrenia (25 men, 23 women) and 48 healthy con-trols (23 men, 25 women), all native Dutch speakers, participated in this study. All patients attended the out-patient clinic of the Schizophrenia Research Unit at the Utrecht University Hospital. The psychiatric diagnosis had been confirmed by an independent psychiatrist via a structured diagnostic interview (the Compre-hensive Assessment of Symptoms and History (Andreasen et al., 1992). All pa-tients satisfied the DSM-IV-R criteria for schizophrenia. To avoid effects of affective symptoms and co-medication on the test-scores, only patients without prominent affective symptoms (e.g. no schizo-affective disorder, no concurrent depression) and no other concomitant axis I disorder were recruited for the study. Most fe-male (n= 22) and male (n=21) patients were diagnosed with the paranoid sub-type of schizophrenia; only 1 female patient and 2 male patients were diagnosed with a disorganized subtype and 2 male patients with a residual subtype. At the time of testing, all patients were required on atypical anti-psychotics without any co-medication, such as tranquilizers or antidepressants.

Patients were studied while at least 6 weeks clinically stable on the same dos-age of medication. Positive and negative symptoms, including their severity, were measured using a structured interview (the Positive And Negative Syndrome Scale (PANSS; Kay et al., 1987), on the day of testing. Male and female patients did not differ significantly in age at first psychosis, the number of hospitalizations, the duration of illness or the dosage of their medication.

The control subjects were either volunteers from the Utrecht University Hos-pital or had been recruited through an advertisement in local newspapers. They had been screened, using the Mini-International Neuropsychiatric Interview Plus

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Table 1. Characteristics of all participants of the Empathizing-Systemizing Questionnaires and IIPT task*

Characteristic Male patients(N=25/23*)

Female Patients(N=23/23*)

Male controls (N=23/24*)

Female controls(N=25/22*)

Mean SD SD Mean SD Mean SDAge (years) 29.4/29.7

(19-40 y)7.2/7.1 31.7/31.7

(20-39 y)6.6/6.6 26.2/26.9

(19-41 y)5.6/6.1 28.9 /29.3

(20-39 y)6.1/6.4

Subjects’ education(1)

2.0/2.1 1.0/1.1 2.4/2.4 1.0/1.0 2.5/2.5 .9/.8 2.4/2.4 .8/.9

NART 106/106 10.6/10.6 109/109 9.8/9.8 109/109 6.1/5.9 106/107 7.2/6.6

Raven 8.0/7.7 2.9/2.9 8.8/8.8 2.2/2.2 9.6/9.6 2.0/2.0 9.6/9.5 1.8/1.9

PANSS Positive Syndrome scale scores(2)

11.4/10.8 4.4/3.9 9.9/9.9 3.2/3.2

PANSS Negative syndrome scale scores(2)

16.5/15.9 6.7/6.9 14.0/14.0 5.3/5.3

PANSS General symptom scores(2)

27.0/25.9 9.0/8.4 24.6/24.6 5.4/5.4

Duration of illness (years)(2)

6.8/6.5 4.5/4.4 8.3/8.3 6.7/6.7

Age at first psychosis(2)

22.6/23.2 5.1/5.3 23.3/23.3 5.3/5.3

Number of hospitalizations(2)

1.7/1.7 1.3/1.3 1.3/1.3 1.2/1.2

Dose of atypical antipsychotics(2,3)

12.1/12.4 4.1/4.2 12.3/12.3 7.2/7.2

(1) Education was measured on a 4-point scale: low (1); middle (2); high (3); university (4).(2) Differences between male and female patients were non-significant(3) Dose of atypical antipsychotics in mg olanzapine equivalents (Dose conversion:

20 mg of olanzapine is equivalent to 6 mg of risperidone, 700 mg of quetiapine, 30 mg aripiprazole or 500 mg of clozapine; ref.: Kohler et al., 2003) Olanzapine (N=21; range = 5-20 mg; mean dose 10 mg) Clozapine (N=11; range = 100-500 mg; mean dose 325 mg = 13 mg equivalent olanzapine) Risperidone (N= 9; range = 1.5-6 mg; mean dose 3.65 mg = 12 mg equivalent olanzapine) Quetiapine (N=1; mean dose 400 mg = 10 mg equivalent olanzapine) Aripiprazole (N= 6; range = 15-30 mg; mean dose 20 mg = 13 mg equivalent olanzapine)

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108 Empathy and perception of social interaction

(MINI-Plus), for current or past psychiatric illness, in themselves or their first-de-gree relatives (Sheehan & Lecrubier, 1998).

All participants were assessed with the Dutch version (Nederlandse Leestest voor Volwassenen, NLV; Schmandt et al., 1992) of the National Adult Reading Test (NART; Nelson, 1982), a test devised to predict pre-morbid intellectual functioning in people suspected of cognitive decline. Scores on the Raven Standard progressive matrices (Raven et al., 1996) were used as an index for nonverbal, performal IQ. Both groups were screened using a medical history questionnaire and interview. Exclusion criteria included a history of neurological or systemic disease, and a di-agnosis of an active substance use disorder in the 3 months prior to study.

Patients and control subjects did not differ significantly in terms of education, pre-morbid estimated IQ (NART), or age within sex, but differed in age between groups and in non-verbal IQ (Raven).

Group characteristics of patients and controls are reported in Table 1.

After receiving a complete description of the study, written informed consent was obtained from the subjects. The Medical Ethics Committee of the University Medical Center Utrecht approved the study.

2.2. Procedure2.2.1. Empathizing- Systemizing Questionnaires Use was made of the Dutch version of the Empathizing-Systemizing Question-naires (Baron-Cohen, 2003), a ‘forced- choice’ self-rating scale developed to in-vestigate sex differences in empathizing and systemizing.

The questionnaires contain 120 items, (40 Systemizing items, with 20 filler items, and 40 Empathizing items with 20 filler items). Items and filler items are randomly dispersed. Filler items are not scored. Scores on each item vary be-tween 0 (disagree), 1 (slightly agree) and 2 (strongly agree), with a range of to-tal scores between 0 and 80.

The Empathizing and Systemizing Questionnaires can be said to have reason-able construct and external validity in having high Cronbach’s alpha’s coefficients (EQ: .92 and SQ: .79) and in being correlated with independent measures (Bar-on-Cohen, 2004).

2.2.2. Interpersonal Information in Postures Task (IIPT)In the Interpersonal Information in Postures Task (IIPT)-negative, all partici-pants were presented with a series of 15 drawings, depicting a social interaction between 2 persons (A and B), followed by the question: ‘Imagine you are figure A. How annoying would it be to person B, to talk to you (person A)?’ Postures showed clear signs of rejection, anger, boredom, discomfort or lack of interest, as indicated by a free labeling task in an earlier study. Scores on each item vary between 0 (not annoying), 1 (a little annoying), 2 (quite annoying) and 3 (very annoying). The IIPT-negative showed a Cronbach alpha coefficient of .79, and a test-retest (interval 4 months) correlation of .70. (van Beek, in prep.)

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See figure 1-4 for some examples of this task.

Figure 1-4.

In the Interpersonal Information in Postures Task (IIPT)-positive all subjects were presented with 11 pairs of drawings, each pair depicting two slightly differ-ent social interactions. Participants were asked again to imagine they were per-son A and to indicate in which of the 2 drawings of each pair, person B enjoyed it more to talk with person A. The two situations differed in indications for close-ness, interest, comfort and interpersonal liking (van Beek, in prep.). Scores on each item varied between 0 (no difference), 1 (difference, drawing 1 most en-joyable), 2 (difference, drawing 2 most enjoyable). The total score indicates the number of correct answers. Test-retest correlation was 0.7.

See figure 5.1 and 5.2 and 6.1 and 6.2 for some examples of this task.

5.1 5.2

6.1 6.2

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110 Empathy and perception of social interaction

2.2.3. Statistical analysisThe scores on the Interpersonal Information in Postures Task and on the Empa-thizing-Systemizing Questionnaires were analyzed by ANOVA’s (Group and Sex). Data analysis on the IIPT-positive was limited to the tests where controls chose the same answer in more than 80% of the scores (pictures 1, 2, 4, 5, 6, 8, 9 and 10). In addition, analyses of co-variance were conducted with age and IQ as co-variates.

Correlation coefficients (Pearson) were computed for associations between pa-tient variables (duration of illness, dosage of medication, PANSS-scores) and Em-pathizing-Systemizing and IIPT data.

3. Results3.1. Clinical variables

As can be seen in Table 1, no significant differences were found between male and female patients in severity of negative symptoms, positive symptoms and general psychopathology sub-scale, measured by the PANSS.

3.2. Empathizing, Systemizing and IIPT scores3.2.1. EmpathizingAn ANOVA on all items showed a main effect of Group (F(df 1,91) = 13.6; p < .001), with higher scores in controls, and of Sex (F(df 1,91) = 5.0; p = .028), with higher scores in females, but no interaction. Age and IQ as covariates re-vealed no effect.

Lower scores on Empathizing correlated with higher negative symptom scores (r = -.357; p = .014) on the PANSS.

3.2.2. SystemizingOn the Systemizing data, a main effect of Sex was found (F(df 1,91) = 27.1; p < .001), with higher scores in men than in women, but no effect of Group and no interaction. Age and IQ as covariates showed no effect.

No correlations were found between Systemizing scores and patient varia-bles.

3.2.3. Interpersonal Information in Postures scoresThe decoding scores on the IIPT-negative, with age and IQ (Raven) as covariates, showed a main effect of IQ (F(df 1,87) = 9.3; p = .003), a main effect of Group (F(df 1,87) = 12.5; p = .001), with higher scores in controls, and an effect of Sex (F(df 1,87) = 4.3; p = .042), with higher scores in women than in men, but no interaction. Age as a covariate revealed no effect. In the whole group, high-er scores on the IIPT-negative significantly correlated with higher Empathizing scores (r = .303; p = .004).

No effect of Group or Sex was found on the IIPT-positive scores, and no in-teraction.

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IQ (Raven) or age as covariates did not show any significant effect on the IIPT-positive scores.

The results of all subjects on the Interpersonal Information in Postures task and Empathizing-Systemizing Questionnaires are listed in Table 2.

Table 2. Scores of Empathizing-Systemizing and Interpersonal Information in Postures task (IIPT) data.

Characteristic Male patients (N=25)

Female patients(N=23)

Male controls(N=23)

Female controls (N=25)

Mean SD Mean SD Mean SD Mean SD

Systemizing quotient

31.7(range 16-58)

12.5 21.2(range 14-35)

8.3 34.9(range 19-61)

11.6 22.9(range 14-48)

8.5

Empathizing quotient

36.1(range 13-53)

10.4 40.8(range 21-57)

9.7 44.3(range 27-61)

8.6 48.1(range 33-69)

9.7

Characteristic Male patients (N=23)

Female patients(N=23)

Male controls(N=24)

Female controls (N=22)

IIPT-negative scores

18.2(range 12-25)

3.3 19.0(range 9-28)

5.4 19.9(range 14-32)

4.5 22.1(range 14-28)

3.9

IIPT-positive scores

7.0(range 4-8)

1.3 7.0(range 5-8)

.9 7.1(range 5-8)

.9 6.9(range 5-8)

1.0

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112 Empathy and perception of social interaction

4. DiscussionThe main aim of this study was to investigate whether the reported female advan-tage in empathic capacity and social perception would be preserved in schizophre-nia. Empathizing-Systemizing (E-S) skills were assessed with the E-S questionnaires developed by Baron-Cohen (1999) and social perception was examined with a novel Interpersonal Information in Postures task.

As expected, empathic abilities were found to be higher in controls than in pa-tients and higher in women than in men. Lower scores on Empathizing correlated significantly with higher negative symptoms. In accordance with earlier findings, men showed significantly higher scores than women on systemizing, but in con-trast to findings in autism (Baron-Cohen et al., 2003), no differences were found between patients and controls.

Regarding the perception of social interactions depicted in schematic draw-ings, on the Interpersonal Information in Postures task (IIPT)-negative controls significantly more often evaluated interactions between the two protagonists as annoying for the conversation partner, than patients did. This may be the result of difficulties in appraisal of social cues in patients with schizophrenia and would be in line with a study by Corrigan & Green, (1993) using 8 short vignettes of in-terpersonal situations, which showed that patients with schizophrenia were less sensitive to interpersonal cues than control subjects. Specifically recognizing ab-stract cues in a low arousal situation was found to be difficult for patients. Other studies reported that patients with schizophrenia have impaired understanding of hints and appropriate levels of politeness (Corcoran & Frith, 1996), or fail to pick up and integrate the right emotional cues (Golan & Baron-Cohen, 2006).

According to sex differences in social cue perception, on the IIPT-negative women were found to significantly more often evaluate interactions as annoy-ing for the other person than men did. This is consistent with a body of evidence implicating that women are more sensitive to subtle non-verbal social cues than men (Constanzo & Archer, 1989; Hall, 1978, 1984, 2000; Nowicki & Duke, 1994; Rosenthal et al., 1979). In the whole group, higher scores on the IIPT-negative correlated with better empathic abilities (r = .303; p = .004). On the IIPT-positive the 4 groups obtained similar scores: all participants were able to choose out of 2 pictures the one that showed the most enjoyable interaction. This comparison task, originally designed for children, might have been too easy for adults.

Findings from neuro-imaging may shed additional light on social cognitive dysfunction in schizophrenia. For example, an fMRI study by Völlm et al., (2006) showed evidence that processing empathy and social cognition stimuli is associat-ed with overlapping (e.g. frontotemporal cortex) but distinct neuronal networks, such as (para)cingulate and amygdala in empathic processing, and the orbito- frontal cortex in ‘Theory of Mind’ tasks. Since some of these brain areas have also been suggested to be compromised in schizophrenia (Wright et al., 2000), impair-ment in different parts of this networks may result in various forms of dysfunc-tion in both (social cognition and empathy) domains. For example, patients with ventromedial frontal lobe injury have been found to show inappropriate social

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manners and a lack of empathy and concern for other people, while patients with amygdala damage have been reported to judge untrustworthy or unapproachable faces as abnormally trustworthy and approachable (Adolphs et al., 1998).

Although several other studies have shown that patients with schizophrenia are impaired in social perception and empathic abilities, in the majority of these studies, use was made of tasks requiring facial or vocal emotion recognition or language processing (e.g. videotapes, dialogues, cartoons), functions that are often impaired in schizophrenia. A noteworthy strength of this study is that the influence of deficits in language processing and facial affect recognition on task performance was avoided by the use of a decoding task in which appraisal of body-language was required in terms of interpersonal meaning. Another strength is the care that was taken to carefully match male and female patients on symptom se-verity. Since female patients generally present with a later age at onset and less severe (negative) symptoms than male patients, a difference in symptom sever-ity otherwise might have become a confounding factor.

A limitation of this study might be that the scores on the Empathizing ques-tionnaire do not actually measure empathic abilities, but reflect the way subjects estimate those abilities in themselves. These responses may be influenced by so-cial desirability and lack of insight in one’s own thoughts and feelings. However, the fact that the Empathizing scores correlated significantly with the scores on the Interpersonal Information in Postures task supports the validity of the Em-pathizing questionnaire. A limitation of the Interpersonal Information in Postures task is that it has been newly developed. Therefore, further validation of the cur-rent results will be necessary.

In summary, patients with schizophrenia are characterized by deficits in em-pathic abilities, but the female advantage in empathy was found to be preserved in patients. Controls are more inclined than patients and women are more in-clined than men, to pick up subtle social cues that may signal the interaction to be annoying for the other person. Since empathic capacity and awareness of the impact of own behavior on other people has been reported to be associated with better social skills (Ihnen et al.,1998), these findings may explain in part the bet-ter course and outcome of female patients with schizophrenia.

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5. ReferencesAdolphs R, Tranel D, Damasio AR. The human amygdala in social judgment. Nature. 1998 Jun 4;393(6684):470-4. Comment in: Nature. 1998 Jun 4;393(6684):417-8.

Adolphs R. Neural systems for recognizing emotion. Curr Opin Neurobiol. 2002 Apr;12(2):169-77.

Andreasen NC, Flaum M, Arndt S. The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 1992;49:615-623.

Baron-Cohen S, Jolliffe T, Mortimore C, Robertson M. Another advanced test of theory of mind: evidence from very high functioning adults with autism or Asperger Syndrome. J Child Psychol Psychiatry 1997;38:813-823.

Baron-Cohen S, Ring H, Wheelwright S, Bullmore E, Brammer M, Simmons A, Williams S. Social intelligence in the normal and the autistic brain: an fMRI study. Eur J Neurosci 1999;11:1891-1898.

Baron-Cohen S. The extreme male brain theory of autism. Trends Cogn Sci 2002;6:248-254.

Baron-Cohen S, Richler J, Bisarya D, Gurunathan N, Wheelwright S. The systemizing quotient: an investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences. Phil. Trans. R. Soc. Lond. 2003;358:361-374.

Baron-Cohen S, Wheelwright S. The empathy quotient: an investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences. J Autism Dev Disord. 2004 Apr;34(2):163-75.

Blair RJ. Responding to the emotions of others: dissociating forms of empathy through the study of typical and psychiatric populations. Conscious Cogn. 2005 Dec;14(4):698-718.

Corcoran R, Frith CD. Conversational conduct and the symptoms of schizophrenia. Cognitive Neuropsychiatry 1996;1:305-318.

Corrigan P, Green M. Schizophrenic patients’ sensitivity to social cues: the role of abstraction. Am J Psychiatry, 1993;150(4):589-594.

Costanzo M, Archer D. Interpreting the expressive behavior of others: The Interpersonal Perception Task. Journal of Nonverbal Behavior. 1989;13:225–245.

Davis M. Empathy: A social psychological approach (Social Psychology Series). Westview Press. 1994.

Page 115: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter five 115

Golan O, Baron-Cohen S. Systemizing empathy: Teaching adults with Asperger syndrome or high functioning autism to recognize complex emotions using interactive multimedia. Dev Psychopathol 2006;18(2):591-617.

Goldstein JM, Lewine RRJ. Overview of sex differences in schizophrenia: where have we been and where do we go from here? In: Castle DJ, McGrath JJ, Kulkarni J. (Eds.), Women and schizophrenia.. Mass. Cambridge University Press, Cambridge. 2000:111-153.

Hall J. Gender effects in decoding nonverbal cues. Psychol Bull 1978;85:845-858.

Hall JA. Nonverbal sex differences: Communication accuracy and expressive style. Baltimore: Johns Hopkins University Press. 1984.

Happe F. The role of age and verbal ability in the theory of mind task performance of subjects with autism. Child Dev 1995;66:843-855.

Hoffman ML. Sex differences in empathy and related behaviors.Psychol Bull. 1977 Jul;84(4):712-22.

Ihnen G, Penn D, Corrigan P, Martin J. Social perception and social skill in schizophrenia. Psychiatry Research 1998;80(3):275-286.

Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale (PANSS). MultiHealth Systems Inc. North Tonawanda, NY. 1986.

Kohler CG, Turner TH, Bilker WB, Brensinger CM, Siegel SJ, Kanes SJ, Gur RE, Gur RCFacial emotion recognition in schizophrenia: intensity effects and error pattern. Am J Psychiatry. 2003;160:1768-1774

Langdon R, Coltheart M, Ward PB. Empathetic perspective-taking is impaired in schizophrenia: evidence from a study of emotion attribution and theory of mind.Cognit Neuropsychiatry. 2006 Mar;11(2):133-55.

Leung A, Chue P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr. Scand. (Suppl.) 2000;101:3-38.

McClure EB. A meta-analytic review of sex differences in facial expression processing and their development in infants, children, and adolescents. Psychol Bull. 2000;126:424-453.

Moran P, Hodgins S. The correlates of comorbid antisocial personality disorder in schizophrenia. Schizophr Bull. 2004;30(4):791-802.

Page 116: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

116 Empathy and perception of social interaction

Nelson HE, Willison J. National Adult Reading Test (NART), Second Edition. 1982.

Nowicki S, Jr., Duke M P. Individual differences in the nonverbal communication of affect: The Diagnostic Analysis of Nonverbal Accuracy Scale. Journal of Nonverbal Behavior. 1994;18:9–36.

Pinkham A, Penn, D, Perkins D, Lieberman J. Implications for the neural basis of social cognition for the study of schizophrenia. Am J Psychiatry 2003;160:815-824.

Raven JC, Court JH, Raven J. Standard progressive matrices: with adult US norms. Oxford: Oxford Psychologists; London: Lewis & Co. 1996.

Rosenthal R, Hall JA, DiMatteo MR, Rogers PL, Archer D. Sensitivity to nonverbal communication: The PONS test. Baltimore: Johns Hopkins University Press. 1979.

Schmand B, Lindeboom J, Harskamp F van. NLV: Nederlandse leestest voor volwassenen: handleiding (NLV) / Lisse: Swets & Zeitlinger 1992.

Scholten M, Aleman A, Montagne B, Kahn R. Schizophrenia and processing of facial emotions: sex matters. Schizophr Res. 2005;78:61-67.

Shamay-Tsoory SG, Tomer R, Goldsher D, Berger BD, Aharon-Peretz J. Impairment in cognitive and affective empathy in patients with brain lesions: anatomical and cognitive correlates. J Clin Exp Neuropsychol. 2004 Nov;26(8):1113-27.

Shamay-Tsoory SG, Tomer R, Berger BD, Aharon-Peretz J. Characterization of empathy deficits following prefrontal brain damage: the role of the right ventromedial prefrontal cortex. J Cogn Neurosci. 2003 Apr 1;15(3):324-37.

Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 1998;59:22-33.

Soderstrom H. Psychopathy as a disorder of empathy. Eur Child Adolesc Psychiatry. 2003 Oct;12(5):249-52.

Völlm BA, Taylor AN, Richardson P, Corcoran R, Stirling J, McKie S, Deakin JF,Elliott R. Neuronal correlates of theory of mind and empathy: a functional magneticresonance imaging study in a nonverbal task. Neuroimage. 2006 Jan 1;29(1):90-8.

Wright I, Rabe-Hesketh S, Woodruff P, David A, Murray R, Bullmore E. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;157:16-25.

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6General Discussion

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General DiscussionThe research in the present thesis focused on examining sex differences in sev-eral domains of emotional processing in patients with schizophrenia compared to healthy controls.

Patients with schizophrenia are known to be impaired in processing facial and vocal emotions and in empathic abilities. These deficits have been associated with impaired social functioning. Since female patients show better social skills than male patients and healthy women outperform men in emotion recognition and empathic capacity, studying sex differences in emotional processing might con-tribute to a better understanding of the differences between men and women in the clinical manifestation of the illness. To this end, sex differences were studied in facial emotion recognition, emotion recognition in prosody and semantics of spoken language; empathy and perception of social interaction; working mem-ory in simultaneous and sequential processing of language and emotion; long-term memory for visual information with positive, negative and neutral content; sensitivity to threat (inhibition) and reward (activation) in relationship to heart-measures.

Emotion recognition In this study (Chapter 2, part 1) we investigated whether the previously re-ported (Hall, 1978, 1984; McClure, 2000) female advantage at identifying facial emotions was preserved in schizophrenia. A clear sex difference was observed in the ability to recognise facial emotions, especially negative ones, with women outperforming men. This female advantage was found to be preserved in schizo-phrenia. Our findings in controls were consistent with previous research in healthy subjects (McClure, 2000); in patients with schizophrenia this study was the first to examine sex differences in facial affect recognition.

The second study on emotion recognition (Chapter 2, part 2) examined whether normal sex differences in emotional language processing, with women outperforming men (Hall, 1978, 1984; McClure, 2000), are preserved in schizo-phrenia. Findings on the language task were contrasted with a visuo-spatial task, in which men typically excel (Linn & Petersen, 1985; Roberts & Bell, 2003). Since general intellectual deficits have been hypothesised to underlie deficits in affect recognition in schizophrenia (Edwards, 2001; Poole, 1999), in addition, the rela-tionship between the results on the language task and the visuo-spatial task and IQ(Raven) scores was studied.

Concerning emotional language processing, healthy controls were found to out-perform patients, and women were found to outperform men on affective prosody, also after correction for IQ. In contrast, controlling for IQ reduced group- and sex differences on emotional semantics to an insignificant trend. In line with previous studies (Fricchione et al., 1986; Leitman et al., 2005), deficits in prosodic process-ing were found to correlate significantly with severity of negative symptoms.

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On the incongruous conditions of the emotional language task (incongruence between emotional tone and emotional content) women outperformed men on affective prosody with distraction of incongruent emotional content, also after correction for IQ. Furthermore, in line with a study by Besson et al. (2002), all participants showed more difficulty in ignoring semantics, while listening to pros-ody, than vice verse. Especially male patients often chose an answer that applied to the ‘to be ignored’ emotional content while listening to prosody.

In confirmation of a previous study by Edwards et al. (2001), we also found that fearful and sad vocal expressions were the most difficult to recognise for all participants.

On the task of visuo-spatial ability, healthy males outperformed healthy fe-males, despite the fact that all women had been tested during menstruation, when oestrogen is low and spatial performance is best (Driscoll et al., 2005). This is in line with previous findings in healthy participants (Burton et al., 2005; Linn & Peterson, 1985; Roberts & Bell, 2003). However, male patients, female patients and female controls obtained similar scores.

Alltogether, these data suggest that men and women employ different cogni-tive strategies in verbal and spatial tasks, which may be based on sexual dimor-phism in brain function. This could imply that the same neurocognitive defects might have different consequences in men and women.

MemoryIn Chapter 3 we tested the hypothesis that male patients are more impaired in the simultaneous and sequential processing of language and emotion than fe-male patients. To this end, all subjects were assessed with 2 emotional working memory tasks and a visual emotional long-term memory task.

One working memory task (Simultaneous Working memory task) tested sensi-tivity to interference and required simultaneous operations in 2 conditions: count-ing out loud while distinguishing between (i) male/female faces and between (ii) facial expressions (anger/fear). Our findings revealed that male, but not female patients were significantly impaired on the emotion condition of this task. The superior performance of female patients relative to male patients on the Simul-taneous Working Memory task may in part be attributed to a female advantage in emotion recognition. However, in contrast to other emotion perception tasks, in this task only two emotions (anger, fear) had to be distinguished, which made the task relatively easy to perform. Furthermore, while the same faces and the same two emotions were used in the Simultaneous Working Memory task as well as in the Sequential Working Memory task, male and female patients performed equally well (but significantly worse than controls) on the emotion condition of the Sequential Working Memory task. This may indicate that sex differences in the ability of emotion recognition are not a crucial (nor a confounding) factor in explaining the sex difference between male and female patients in the simulta-neous Working Memory task. Another explanation might be that men and women

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activate different brain area’s in completing Working Memory tasks. For exam-ple, Speck et al., (2000) found right-lateralised or bilateral activation in male subjects, and predominantly left hemispheric activation in female subjects in a verbal Working Memory task, in the absence of sex differences in performance. Simultaneously performing a facial emotion recognition task (which is supposed to be right lateralised) and a verbal Working Memory task (relatively left lateral-ised in women, and right lateralised in men), might cause more interference in men than in women, and result in impaired performance in male patients when Working Memory capacity is compromised by schizophrenia.

On the second working memory task (Sequential Working Memory task), all participants subsequently had to identify and hold on line 3 types of information (mathematics, male-female faces and the facial emotions anger-fear) and to com-pare that information with verbal material. Patients performed significantly worse relative to controls on facial emotions, but not on mathematics. These findings indicate that especially the processing of emotions is impaired in schizophrenia. This might be due to the fact that schizophrenia has been associated with dys-function of right hemisphere regions involved in emotion processing (Borod et al., 1993; Cutting, 1991, 1992; Kucharska-Pietura et al., 2002; Ross et al., 2001), while processing mathematics and semantics are both more left lateralised.

No sex differences were observed in any of the conditions. This might imply that women do not benefit from their advantage in emotion recognition when more complex working memory activities are required.

On the Long-term Memory task, which tested the ability to recognize pictures with a neutral, positive and negative content after 1 hour delay, male and female patients were found to be equally impaired. Type of emotion that was shown in the picture (positive or negative) did not make any difference in accuracy scores between the sexes. This may suggest a more generalized memory deficit in pa-tients than a specific deficit in processing emotion. Our findings are in line with previous studies reporting deficits in verbal (Berenbaum et al., 1997; Herlitz et al., 1997) and visual (Aleman et al., 1999) memory in schizophrenia.

In summary, men, but not women, with schizophrenia were found to be signif-icantly impaired in performing a simultaneous language/emotion Working Mem-ory task. However, in more complex sequential or long-term processing of visual and verbal, neutral and emotional stimuli, no female advantage was observed.

Behavioral Inhibition and ActivationThe study in Chapter 4 examined sensitivity to punishment (Behavioral Inhibi-tion System; BIS) and reward (Behavioral Activation System; BAS) in patients with schizophrenia compared to controls. In addition, we analyzed psychophysi-ological measures of average heart rate (HR) and heart rate variability (HRV) in both groups, and their relationship to BIS/BAS scores and symptomatology. Pa-tients showed a higher sensitivity to threat than controls. This higher BIS sensi-tivity correlated with longer duration of illness and lower scores on the negative PANSS symptoms. The results on the BIS scale confirmed our hypothesis that

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patients with schizophrenia show increased sensitivity to cues of threat and non-reward. Dispositional responsiveness to threat may cause a bias toward identifi-cation of emotional stimuli as negative and may result in impaired regulation of social behaviour.

In contrast to our expectations, and to findings in a previous study by Leone et al., (2001), no sex differences were found on the BIS.

BAS scores were expected to vary with the positive (high BAS) and negative symptoms (low BAS) on the PANSS. However, no differences were found in sensi-tivity to reward (BAS) between patients and controls and between men and wom-en. Since all patients had been treated with atypical antipsychotic medications, and the BAS is supposed to control reward sensitivity via dopaminergic activity, medication may have influenced the results. Indeed, a correlation between BAS-sensitivity and dosage of medication was found, implying that patients with high-er BAS sensitivity also were treated with a higher dosage of medication.

Scores on the psychophysiological measures showed a higher average heart rate (HR) and lower heart rate variability (HRV) in patients, indicating reduced parasympathetic activity (Malaspina et al., 2002; Toichi et al., 1997) and higher autonomic arousal (Zahn et al., 1981a, 1981b, 1997). Further analyses showed that this finding was limited to patients treated with clozapine, which is in line with a study by Rechlin (1995) reporting no differences in HRV parameters be-tween patients and controls, and with several studies (Agelink et al., 2001; Cohen et al., 2001; Eschweiler et al., 2002), showing significantly higher HR and lower HRV in clozapine-treated patients compared to controls or compared to patients using olanzapine. No correlations were been found between psychophysiological measures and dosage of medication.

Our hypothesis that high BIS sensitivy would correlate with the cardiac meas-ures (increased HR and decreased HRV) was not confirmed, since no correlations between BIS/ BAS scores and HR/HRV scores have been found. Results from a study by Dishman et al., (2000) in healthy men and women, suggested that re-cent experience of emotional stress, but not trait anxiety, influenced HRV meas-ures. Carver and White (1994) also have asserted that the BIS scale is not strongly related to state anxiety measures, since it primarily reflects a trait characteristic, i.e. sensitivity towards stress, rather than the way anxiety is experienced.

In conclusion, the results of this study demonstrated that male and female pa-tients with schizophrenia are more sensitive to threat than control subjects and are more likely to regard stimuli as threatening. This may imply that schizophre-nia is characterized by a vulnerability to anxiety, which may in turn be a pathway to psychosis. High BIS sensitivity may reflect a trait-related characteristic, and is not reflected in state-related psychophysiological measures.

Empathy and perception of social interactionThe main aim of this study (Chapter 5) was to investigate whether the female advantage in empathic capacity (assessed with the Emphathizing-Systemizing (E-S) questionnaires developed by Baron-Cohen; 2004) and in the perception of

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social interaction (examined with a novel Interpersonal Information in Postures Task; IIPT), was preserved in schizophrenia.

Empathic abilities were found to be higher in controls than in patients and higher in women than in men men. Lower scores on Empathizing correlated sig-nificantly with higher negative symptoms. In contrast to findings in autism, Sys-temizing data did not reveal differences between patients and controls, but men showed significantly higher scores than women across groups. The findings on empathy in controls were in line with previous studies (Baron-Cohen, 1997, 2002; Davis, 1994). Our study was the first to examine sex differences on empathy in schizophrenia.

On the IIPT-negative (‘how annoying would it be to person B to talk to A?’), controls significantly more often evaluated interactions as annoying for the con-versation partner than patients. The same was found for women compared to men. On the whole group, higher scores on the IIPT-negative correlated with better empathic abilities. On the IIPT positive (‘in which of these two pictures is the contact with A the most enjoyable to B?’), the four groups obtained simi-lar scores: all participants were able to choose out of two pictures the one that showed the most enjoyable interaction. In both parts of the IIPT an emotional judgement was required on the basis of body-language and/or distance between the depicted characters.

These findings might indicate that patients are able to judge social cues cor-rectly when comparing two slightly different social interactions. However, when they have to weigh a single social interaction, patients show a tendency to judge that interaction as less annoying than controls. This may be the result of difficul-ties in appraisal of social cues and would be in line with other studies reporting that patients with schizophrenia fail to pick up and integrate the right emotional cues (Corcoran & Frith,1996; Corrigan et al., 1993; Golan et al., 2006). Some brain areas implicated in processing empathy and social stimuli (Völlm et al., 2006), have been suggested to be compromised in schizophrenia (Wright et al., 2000). For example, patients with ventromedial frontal lobe injury have been found to show inappropriate social manners and a lack of empathy and concern for other people, while patients with amygdala damage have been reported to judge un-trustworthy or unapproachable faces as abnormally trustworthy and approacha-ble (Adolphs et al., 1998).

In summary, patients with schizophrenia are characterized by deficits in em-pathic abilities, but the female advantage in empathy was found to be preserved in patients. Furthermore, controls showed a stronger tendency than patients and women were more inclined than men, to judge a social interaction with them-selves as annoying for the other person.

Main findingsThe results of all studies in this thesis have shown that both male and female patients are impaired in several domains of emotional processing. However, on tasks in which women are known to excel, such as emotion recognition in fac-

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es and in language (Chapter 2), and in empathic abilities or perception of so-cial interaction (Chapter 4), the superior performance in women as compared to men was found to be preserved. Preservation of this advantage in female pa-tients was in line with our expectations and may explain, in part, why social func-tioning is less compromised in women with schizophrenia than in men. To our knowledge, these were the first studies on sex differences in facial affect recog-nition and empathy in patients with schizophrenia. Our findings are supported by the results of a recent study by van ‘t Wout et al., (2006) on alexithymia, as-sessed with the Bermond-Vorst Alexithymia Questionnaire, which showed that particularly male patients with schizohrenia demonstrated difficulty in identifying and verbalizing emotions. One other study (Bozikas et al., 2006) investigated sex differences in recognizing prosody, and reported only male patients with schizo-phrenia to be impaired, while female patients showed deficits in just recognizing sadness. This discrepancy may be explained by differences in patient variables between male and female patients (or by the small number of women included in the Bozikas study, which limits statistical power). Notably, in our sample, male and female patients did not differ in age at first psychosis, although age at onset is usually higher in women compared to men (Häfner et al., 1994, 2003). Since lower prosody scores were found to correlate with younger age of first psychosis this might explain why in our sample deficits in prosodic perception were shown in both male and female patients.

Although the exact neural underpinnings of sex differences in emotion recog-nition remain unknown, there is evidence that men and women differ in their ba-sic patterns of brain activation in processing (facial) affect (Shucard et al., 1981; Shucard & Shucard, 1990; Everhart, 2001) and language (Baxter et al., 2003; Rossell et al., 2002; Shaywitz et al., 1995). In addition, in schizophrenia some ab-normal reversal of lateralisation in speech processing have been reported, which may impact differently on both sexes. However, our findings on both emotion recognition tasks did not reveal changes in sex differences on performance, but showed preservation of the normal sex differences in the illness.

In contrast to our findings that the female advantage on emotion recognition was preserved in schizophrenia, the male advantage on visuo-spatial ability was found to be lost. Low oestrogen levels, reported in women with schizophrenia, ir-respective of antipsychotic induced hyerprolactinemia (Bergemann et al., 2005), may have facilitated visuo-spatial performance in the female patients. Further-more, there is evidence that mental rotation ability is positively related to the magnitude of right hemispheric specialisation (Siegel-Hinson & McKeever, 2002) and that men and women differ in cerebral activation patterns during mental ro-tation (Jordan et al., 2002; Weiss et al., 2003), with right hemispheric advantage in men, but not in women (Rilea et al., 2004). Since schizophrenia has been asso-ciated with right hemisphere dysfunction (Borod et al., 1993; Cutting, 1992; Ku-charska-Pietura et al., 2002; Ross et al., 2001), this will have stronger implications for spatial ability in (right lateralised) male patients than in female patients.

Our results on the mental rotation task are in contrast with a study by Halari et al. (2006), which demonstrated that sexual dimorphism on a spatial

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task (favoring men), remains intact in patients with schizophrenia. This discrep-ancy may be explained by sample differences between the studies. Compared to the study by Halari, the duration of illness was shorter (8.5 versus 21.5 years) in the female patients of our study, which may have advanced preservation of their cognitive skills. Furthermore, the patients in Halari’s study were all treated with typical anti-psychotics, while in our study all patients were on atypical anti-psy-chotic medication. Improvement on verbal tasks (Buchanan et al., 1994; Mull-er et al., 2005) and on spatial tasks (Gur et al., 2003; Harvey et al., 2003) has been linked to treatment with atypical anti-psychotic medication, but not typical anti-psychotics. Moreover, female patients have been reported to show a better treatment response to anti-psychotics relative to male patients (Goldstein et al., 2002). These factors might explain why we found preservation of sexual dimor-phism on the verbal task in female patients, and loss of sexual dimorphism on the spatial task in male patients with schizophrenia.

Cognitive functioning was found to largely account for the group- and sex dif-ferences in processing emotional semantics, but not for the group- and sex dif-ferences in processing emotional prosody (Chapter 2). This might indicate that non-verbal processing of emotional information is related to specific brain struc-tures and is relatively independent of cognitive functioning. How important the role of cognitive deficits may be in the processing of emotional information, was shown in Chapter 3. When more complex activities were required, e.g. encod-ing or storage of information as in sequential or long-term processing of stimuli, male and female patients both performed significantly worse relative to controls. No female advantage was observed, and women did not appear to benefit from their advantage in emotion recognition, due to impairment of working memory and long-term memory function. Our findings are in line with a study by Haut & Barch (2006) which showed no sex differences in memory processing in healthy participants. In addition, in a study by Hoff et al., (1998) no sex differences in cognitive function were reported between male and female patients when sam-ples were matched on symptom severity.

On the sequential processing of mathematics and language (Chapter 3), pa-tients and controls obtained similar scores, which indicates that particularly the processing of emotions is impaired in schizophrenia. This might be due to the fact that emotional input has been found to undergo more processing than non-affective stimuli at a relatively early stage in cortical afferent analysis (Irwin et al., 1996), and requires more working memory load. However, on a task of simultaneously processing affective visual and neutral verbal information (Chapter 3) only male patients were found to be impaired. The most important difference between the sequential and the simultaneous task is that in the latter one no encoding, stor-age, or ‘holding online’ of information is required, but that the attention load has to be divided over two activities. As in the affect recognition tasks, more complex cognitive processing does not seem to play a major role in this process.

Regarding appraisal to external stimuli, higher sensitivity to threat was found in both male and female patients (Chapter 4). This may imply that schizophrenia is characterized by a vulnerability to internalizing problems, anxiety and depres-

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sion, which may in turn be a pathway to (paranoid) psychosis, since the evalua-tion of external stimuli tends to be too negative. The higher sensitivity to threat was not associated with higher arousal on cardiovascular measures and appears to be more a measure of trait than of state.

On the other hand, patients were found to be more inclined to interpret an ambiguous social interaction, on the basis of body language, as not annoying for the conversation partner than controls did (Chapter 5). This is in line with pre-vious studies reporting misinterpretation of social cues (Corcoran & Frith,1996; Corrigan et al., 1993; Golan et al., 2006) or interpretation of facial expressions as too trustworthy (Adolphs et al., 1998).

The same was found for men compared to women: men showed a higher tendency to interpret an interaction as not annoying for the other person than women. Women appear to be more sensitive for subtle social cues in body lan-guage and physical distance between subjects than men. This difference was found to be preserved in schizophrenia.

Methodological considerationsSample selectionEarly age at onset is associated with a higher severity of negative symptoms, which in turn is related to stronger impairment in emotional processing and social skills. Male patients usually fall ill earlier and show more severe negative symp-toms than female patients. Since we wanted to investigate whether the female advantage in emotional processing was preserved in schizophrenia, care was tak-en to avoid confounding effects of symptom severity. Therefore, male and female patients were carefully matched on age of onset, severity of symptoms and dos-age of medication. Thus, the female patients in these studies may be considered to be relatively ill, since they generally present at a later age at onset and with less severe negative symptoms than male patients. Despite this fact, female pa-tients outperformed male patients on all dimorphic tasks.

Sample bias also concerned the selection of patient characteristics. Our samples consisted of stabilized outpatients on atypical anti-psychotics, without co-medica-tion, recent drug abuse or co-morbid affective symptoms. Acutely ill patients (who are often medication-free or medication-naive) were excluded, because they are most of the time not able to accomplish the tasks, and are more likely to provide information about state differences than about trait differences between male and female patients. Furthermore, chronically disabled patients were not included, because in a chronic disabled sample sex effects tend to attenuate (Goldstein& Lewine, 2000). At the time of testing, all patients were taking atypical anti-psy-chotics without any co-medication, such as tranquilizers, antidepressants, and anticholinergics, since medication with sedative or anticholinergic properties may adversely affect memory (Blanchard & Neale, 1992; Spohn & Strauss, 1989), or may influence affect recognition (Coupland et al., 2004).

Excluding patients with co-morbid disorders or medication may be a limita-tion, in particular in the BIS/BAS study (chapter 4). With regard to the BAS scores

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one might expect higher sensitivities in medication-free patients with psychotic symptoms or manic symptoms, and in psychotic patients with antisocial tenden-cies. On the BIS, higher scores would be expected in patients with a co-morbid affective disorder. Since women show a higher ratio in developing affective symp-toms, excluding patients (and controls) with a (history of) an affective disorder might have attenuated the BIS scores in general and the sex differences in BIS scores in particular. Another limitation might be that we only included patients and healthy controls, and no relatives of patients or controls at high risk. A fu-ture study involving relatives of patients with schizophrenia may reveal if sensi-tivity to threat is a risk factor in this group.

Task selectionWith regard to the tasks that were used, a limitation might be that most tasks were easy to perform. In the control subjects, the low level of difficulty of some tasks may have caused ceiling effects, obscuring potential sex differences, for example in the Simultaneous Working Memory task (chapter 3) and in the Semantic task with prosodic distraction (chapter 2). A weakness of the study on empathy and perception of social interaction (chapter 5) might be that the Empathizing-Sys-temizing questionnaires do not actually measure empathic behavior, but the way people report how they would think, feel and act in a specific situation. Further-more, the Interpersonal Information in Postures Task is a newly developed task and a further validation of the current results is necessary. However, a notewor-thy strength of this study is that the influence of deficits in language processing and facial emotion recognition on task performance was avoided since (non-ver-bal) appraisal of body-language was required. In the majority of previous stud-ies, showing impairment in social cognition and empathic abilities in patients with schizophrenia, use was made of tasks requiring facial or vocal emotion recogni-tion or language processing (e.g. videotapes, dialogues, cartoons), functions that are often impaired in schizophrenia.

Despite the limitations that were mentioned above in patient- and task selec-tion, significant differences were found between patients and controls on all tasks involving emotional processing.

Clinical implications and future directionsDeficits in emotion processing are a hallmark of schizophrenia and may lead to misunderstanding of social communication and to difficulties in social adjustment. The studies in this thesis have shown that some deficits in emotional processing are more specific (e.g. recognizing affective prosody), while others can be ex-plained in terms of general cognitive impairment (e.g. emotional memory). In ad-dition, deficits were found to be associated with symptomatology. For example, high scores on negative symptoms were associated with more impaired emotion recognition and low BIS sensitivity. A recent study by Gur et al., (2006) report-ed that in particular patients with flat affect showed greater impairment in emo-

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tion processing tasks, identifying emotions and differentiating among intensities within these emotions.

An emerging body of research has shown that emotion recognition and cognitive function in schizophrenia can be improved through (computer assisted) remedi-ation programs. New training tools for remediation of impaired emotion recogni-tion have been developed, such as the ‘micro-expressions training tool’ (METT; Russell et al., 2006) and the ‘Tackling Affect Recognition’ training program (TAR; Wolwer et al., 2005), and have been found to be effective in improving affect rec-ognition. In addition, there is some evidence that the training of verbal-semantic encoding in patients with schizophrenia may improve the ability to identify social cues (Corrigan et al., 1995).

Furthermore, Cognitive Remediation Training programs (e.g. Neurocognitive Enhancement Therapy; NET) have led to significant improvements in perform-ance on memory (Bell et al., 2004) and working memory (Bell et al., 2003) tasks, with enduring effects after 6 months. These findings suggest that specific prac-tice in neurocognitive exercises that are targeted at attention, memory, execu-tive functioning and language, produce improvement in neurocognitive function. In addition, patients receiving Cognitive Remediation Therapy also showed im-provement in social functioning after 6 months follow-up (Penades et al., 2006). However, affect recognition did not improve under Cognitive Remediation Thera-py, suggesting that the above mentioned specific training programs for emotion recognition may be a valuable adjunct to the more cognitive oriented programs. Since male patients are more impaired in affect recognition than female patients, it may be advisable to specifically tailor emotion recognition training programs to the needs of male patients.

The high BIS sensitivities (sensitivity to threat) that were found in our study in patients with schizophrenia may also have clinical implications for treatment and relapse prevention. For example, a tendency to misinterpret emotional in-formation as more threatening, might benefit from cognitive-behavioral therapy, stress-management, or treatment with Selective Serotonin Reuptake Inhibitors (SSRI’s). Biases towards threatening stimuli, with negative distortions in infor-mation processing, have also been reported in patients with anxiety disorder (Mogg & Bradley, 2002; Mogg et al., 1995) and depression (Beck et al., 1979) and have been associated with abnormal amygdala activation. The amygdala ap-pears to play a particular role in the processing of fear relevant cues (Calder et al., 2001). Antidepressant drugs were found to normalize abnormal amygdala ac-tivation (Sheline et al., 2001) and to reduce negative biases in social perception in depressed (Bhagwagar et al., 2004) and anxious patients (Mogg et al., 2004). In healthy volunteers, antidepressants increased memory for positive valenced items and affiliate behaviors (Knutson et al., 1998) and reduced the processing of negative emotional material (Harmer et al., 2004). Further studies will be need-ed in patient with schizophrenia to explore how changes in emotional processing through pharmacological treatment relate to alterations in subjective experience and clinical state. In addition, the use of brain imaging will allow in vivo assess-

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ment of the role of the amygdala in the effects of antidepressant drugs on emo-tional processing.

Regarding the etiology of sex differences in the expression of schizophrenia, the majority of studies suggests that differences in the development of the brain between males and females, regulated by sex steroid hormones, is in the basis of sex differences in behavior and performance and also in the manifestation of the illness. Thus, sex differences in schizophrenia may be in part the consequence of the normal sexual brain dimorphism, due to which men and women differen-tially recruit particular brain regions to perform specific cognitive and emotional tasks. Our results seem to confirm this hypothesis, since tasks in which sex dif-ferences were shown in healthy subjects also showed (the same) sex differences in patients. On the other hand early disruption of brain development in schizo-phrenia will be influenced in different ways in men and women because of the dif-ferences in effects of sex hormones on the brain, and may cause sex differences in (the development of) brain abnormalities in schizophrenia. Especially oestro-gens may play a critical neuroprotective role against neurodegenrative diseases (Garcia-Segura et al., 2006; Whise et al., 2005).

However, studying sex differences in morphology and function of the brain and the influence of sex hormones on these processes is still in its infancy. Bet-ter understanding of brain development and sex effects in healthy subjects will be necessary to understand the impact of sex on schizophrenia and other neurode-velopmental disorders, since the sex effect may not be specific to schizophrenia. Animal studies can be used to test specific hypotheses on organizational and ac-tivational effects of sex steroid hormones on brain structures and function, and fMRI studies may reveal whether men and women, and male and female patients with schizophrenia, differentially recruit particular brain regions to perform spe-cific cognitive or emotional tasks.

In summary, in this thesis we studied sex differences in emotional processs-ing in patients with schizophrenia and healthy controls. Patients were found to be significantly impaired on all emotional tasks, while sex differences in various domains of emotion processing, favoring women, were found to be preserved. Ultimately, a better understanding of the expression and nature of sex effects in schizophrenia may contribute to the development of a more sex-specific treat-ment of this disabling condition.

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ReferencesAdolphs R, Tranel D, Damasio AR. The human amygdala in social judgment. Nature. 1998 Jun 4;393(6684):470-4. Comment in: Nature 1998;393(6684):417-418.

Agelink MW, Majewski T, Wurthmann C, Lukas K, Ullrich H, Linka T, Klieser E. Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine. J Clin Psychopharmacol 2001;21(1):8-13.

Aleman A, Hijman R, Haan EH de, Kahn RS. Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry 1999;156(9):1358-1366.

Baron-Cohen S, Jolliffe T, Mortimore C, Robertson M. Another advanced test of theory of mind: evidence from very high functioning adults with autism or Asperger Syndrome. J Child Psychol Psychiatry 1997;38:813-823.

Baron-Cohen S. The extreme male brain theory of autism. Trends Cogn Sci 2002;6:248-254.

Baron-Cohen S, Wheelwright S. The empathy quotient: an investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences. J Autism Dev Disord 2004;34(2):163-175.

Baxter LC, Saykin AJ, Flashman LA, Johnson SC, Guerin SJ, Babcock DR, Wishart HA. Sex differences in semantic language processing: a functional MRI study. Brain and Language 2003;84(2):264-272.

Beck AT, Rush AJ, Shaw BF, Emery G. Cognitive therapy of depression. New York: Guilford, 1979.

Bell M, Bryson G, Wexler BE. Cognitive remediation of working memory deficits: durability of training effects in severely impaired and less severely impaired schizophrenia. Acta Psychiatr Scand 2003;108(2):101-109.

Bell MD, Fiszdon J, Bryson G, Wexler BE. Effects of neurocognitive enhancement therapy in schizophrenia: normalisation of memory performance. Cognit Neuropsychiatry 2004;9(3):199-211.

Berenbaum S, Baxter L, Seidenberg M, Hermann B. Role of the hippocampus in verbal memory outcome following left anterior temporal lobectomy. Neuropsychology 1997;11: 585-591.

Bergemann N, Mundt C, Parzer P, Jannakos I, Nagl I, Salbach B, Klinga K, Runnebaum B, Resch F. Plasma concentrations of estradiol in women suffering from schizophrenia

Page 132: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

132 General Discussion

treated with conventional versus atypical antipsychotics. Schizophr Res 2005;73(2-3):357-366.

Besson M, Magne C, Schon D. Emotional prosody: sex differences in sensitivity to speech melody. Trends in Cognitive Science 2002;6(10):405-407.

Bhagwagar Z, Cowen PJ, Goodwin GM, Harmer CJ. Normalization of enhanced fear recognition by acute SSRI treatment in subjects with a previous history of depression. Am J Psychiatry 2004;161(1):166-168.

Blanchard JJ, Neale JM. Medication status of participants in psychopathology research: selective review of current reporting practices. J Abnorm Psychol 1992;101(4):732-734.

Borod JC, Martin CC, Alpert M, Brozgold A, Welkowitz J. Perception of facial emotion in schizophrenic and right brain-damaged patients. J of Nervous and Mental Disease 1993;181:494-502.

Bozikas VP, Kosmidis MH, Anezoulaki D, Giannakou M, Andreou C, Karavatos A. Impaired perception of affective prosody in schizophrenia. Journal of Neuropsychiatry and Clinical Neurosciences 2006;18(1):81-85.

Buchanan RW, Holstein C, Breier A. The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance. Biol Psychiatry 1994; 36(11):717-725.

Burton LA, Henninger D, Hafetz J. Gender differences in relations of mental rotation, verbal fluency, and SAT scores to finger length ratios as hormonal indexes. Developmental Neuropsychology 2005;1:493-505.

Calder AJ, Lawrence AD, Young AW. Neuropsychology of fear and loathing. Nat Rev Neurosci 2001;2(5):352-363.

Carver CS, White TL. Behavioural Inhibition, Behavioural Activation, and Affective responses to Impending Reward and Punishment: The BIS/BAS scales. 1994;67:319-333.

Cohen H, Loewenthal U, Matar M, Kotler M. Association of autonomic dysfunction and clozapine. Heart rate variability and risk for sudden death in patients with schizophrenia on long-term psychotropic medication. Br J Psychiatry 2001;179:167-171.

Corcoran R, Frith CD. Conversational conduct and the symptoms of schizophrenia. Cognitive Neuropsychiatry 1996;1:305-318.

Corrigan P, Green M. Schizophrenic patients’ sensitivity to social cues: the role of abstraction. Am J Psychiatry 1993;150(4):589-594.

Page 133: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter six 133

Corrigan PW, Hirschbeck JN, Wolfe M Memory and vigilance training to improve social perception in schizophrenia. Schizophr Res 1995;17(3):257-265.

Cutting J. Delusional misidentification and the role of the right hemisphere in the appreciation of identity. Br J Psychiatry 1991;(Suppl)14:70-75.

Cutting J. The role of right hemisphere dysfunction in psychiatric disorders. Br J Psychiatry 1992;160:583-588.

Coupland NJ, Sustrik RA, Ting P, Li D, Hartfeil M, Singh AJ, Blair RJ. Positive and negative affect differentially influence identification of facial emotions. Depress Anxiety. 2004;19(1):31-34.

Davis M. Empathy: A social psychological approach (Social Psychology Series) 1994 Westview Press.

Dishman RK, Nakamura Y, Garcia ME, Thompson RW, Dunn AL, Blair SN. Heart rate variability, trait anxiety, and perceived stress among physically fit men and women. Int J Psychophysiol 2000;37(2):121-133.

Driscoll I, Hamilton DA, Yeo RA, Brooks WM, Sutherland RJ. Virtual navigation in humans: the impact of age, sex, and hormones on place learning. Hormones and Behavior 2005;47(3):326-335.

Edwards J, Jackson HJ, Pattison PE. Emotion recognition via facial expression and affective prosody in schizophrenia: a methodological review. Clinical Psychology Review 2002;22:789-832. Erratum in: Clinical Psychology Review 2002;22:1267-1285.

Eschweiler GW, Bartels M, Langle G, Wild B, Gaertner I, Nickola M. Heart-rate variability (HRV) in the ECG trace of routine EEGs: fast monitoring for the anticholinergic effects of clozapine and olanzapine? Pharmacopsychiatry 2002;35(3):96-100.

Everhart DE, Shucard JL, Quatrin T, Shucard DW. Sex-related differences in event-related potentials, face recognition, and facial affect processing in prepubertal children. Neuropsychology 2001;15:329-341.

Fricchione G, Sedler MJ, Shukla S. Aprosodia in eight schizophrenic patients. Am J Psychiatry 1986;143(11):1457-1459.

Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection by estradiol. Prog Neurobiol 2001;63(1):29-60.

Golan O, Baron-Cohen S. Systemizing empathy: Teaching adults with Asperger syndrome or high functioning autism to recognize complex emotions using interactive multimedia. Dev Psychopathol 2006;18(2):591-617.

Page 134: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

134 General Discussion

Goldstein JM, Cohen LS, Horton NJ, Lee H, Andersen S, Tohen M, Crawford A, Tollefson G. Sex differences in clinical response to olanzapine compared with haloperidol. Psychiatry Res 2002;110(1):27-37.

Goldstein JM, Lewine RRJ. Overview of sex differences in schizophrenia: where have we been and where do we go from here? In: Castle D.J., McGrath J.J., Kulkarni J. (Eds.), Women and schizophrenia. Mass. Cambridge University Press, Cambridge, 2000:111-143.

Gur RE, Kohler C, Ragland JD, Siegel SJ, Bilker WB, Loughead J, Phend N, Gur RC. Neurocognitive performance and clinical changes in olanzapine-treated patients with schizophrenia. Neuropsychopharmacology. 2003;28(11):2029-2036.

Gur RE, Kohler CG, Ragland JD, Siegel SJ, Lesko K, Bilker WB, Gur RC. Flat affect in schizophrenia: relation to emotion processing and neurocognitive measures. Schizophr Bull 2006;32(2):279-287.

Häfner H, Maurer K, Löffler W, Fätkenheuer B, Heiden an der W, Riecher-Rössler A, Behrens S, Gattaz, W. The epidemiology of early schizophrenia. Influence of age and gender on onset and early course. Br J Psychiatry 1994;164(Suppl 23):29-38.

Häfner H. Gender differences in schizophrenia. Psychoneuroendocrinology 2003;28 (Suppl 2):17-54.

Halari R, Mehrotra R, Sharma T, Ng V, Kumari V. Cognitive impairment but preservation of sexual dimorphism in cognitive abilities in chronic schizophrenia. Psychiatry Res 2006; 141(2):129-139.

Hall J. Gender effects in decoding nonverbal cues. Psychol Bull 1978;85:845-858.

Hall JA. Nonverbal sex differences: Communication accuracy and expressive style. Baltimore: Johns Hopkins University Press, 1984.

Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM. Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Am J Psychiatry 2004;161(7):1256-1263.

Harvey PD, Napolitano JA, Mao L, Gharabawi G. Comparative effects of risperidone and olanzapine on cognition in elderly patients with schizophrenia or schizoaffective disorder. Int J of Geriatric Psychiatry 2003;18(9):820-829.

Haut KM, Barch DM. Sex influences om material-sensitive functional lateralization in working and episodic memory: Men and women are not all that different NeuroImage. 2006;32:411-422.

Page 135: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter six 135

Herlitz A, Nilsson L, Backman L. Gender differences in episodic memory. Memory & Cognition 1997;25:801-811.

Hoff AL, Wieneke M, Faustman WO, Horon R, Sakuma M, Blankfeld H, Espinoza S, DeLisi LE. . Sex differences in neuropsychological functioning of first-episode and chronically ill schizophrenic patients. Am J Psychiatry 1998;155(10):1437-1439.

Irwin W, Davidson RJ, Lowe MJ, Mock BJ, Sorenson JA, Turski PA. Human amygdala activation detected with echo-planar functional magnetic resonance imaging. Neuroreport 1996;7:1765-1769.

Jordan K, Wustenberg T, Heinze HJ, Peters M, Jancke L. Women and men exhibit different cortical activation patterns during mental rotation tasks. Neuropsychologia 2002;40(13):2397-2408.

Knutson B, Wolkowitz OM, Cole SW, Chan T, Moore EA, Johnson RC, Terpstra J, Turner RA, Reus VI. Selective alteration of personality and social behavior by serotonergic intervention. Am J Psychiatry 1998;155(3):373-379. Comment in: Am J Psychiatry 1999 ;156(6):985.

Kucharska-Pietura K, David AS, Dropko P, Klimkowski M. The perception of emotional chimeric faces in schizophrenia: further evidence of right hemisphere dysfunction. Neuropsychiatry Neuropsychol Behav Neurol 2002;15:72-78.

Leitman DI, Foxe JJ, Butler PD, Saperstein A, Revheim N, Javitt DC. Sensory contributions to impaired prosodic processing in schizophrenia. Biol Psychiatry 2005;58(1):56-61.

Leone L, Perugini M, Bagozzi RP, Pierro A, Mannetti L. Construct validity and generalizability of the Carver-White Behavioural Inhibition System / Behavioural Activation System Scales. European Journal of Personality 2001;15:373-390.

Linn MC, Petersen, AC. Emergence and characterization of sex differences in spatial ability: a meta-analysis. Child Development 1985;56(6):1479-1498.

Malaspina D, Dalack G, Leitman D, Corcoran C, Amador XF, Yale S, Glassman A, Gorman JM. Low heart rate variability is not caused by typical neuroleptics in schizophrenia patients. CNS Spectr 2002;7(1):53-57.

McClure EBA meta-analytic review of sex differences in facial expression processing and their development in infants, children, and adolescents. Psychol Bull 2000;126:424-453.

Mogg K, Bradley BP, Millar N, White J. A follow-up study of cognitive bias in generalized anxiety disorder. Behav Res Ther 1995;33(8):927-935.

Page 136: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

136 General Discussion

Mogg K, Bradley BP. Selective orienting of attention to masked threat faces in social anxiety. Behav Res Ther 2002;40(12):1403-1414.

Mogg K, Baldwin DS, Brodrick P, Bradley BP. Effect of short-term SSRI treatment on cognitive bias in generalised anxiety disorder. Psychopharmacology (Berl) 2004;176(3-4):466-470.

Muller U, Werheid K, Hammerstein E, Jungmann S, Becker T. Prefrontal cognitive deficits in patients with schizophrenia treated with atypical or conventional antipsychotics. European Psychiatry 2005;20(1):70-73.

Penades R, Catalan R, Salamero M, Boget T, Puig O, Guarch J, Gasto C. Cognitive remediation therapy for outpatients with chronic schizophrenia: a controlled and randomized study. Schizophr Res 2006;87(1-3):323-331.

Poole JH, Tobias F, Vinogradow S. The functional relevance of affect recognition errors in schizophrenia. Journal of the International Neuropsychological Society 2000;6:649-658.

Rechlin T. Effects of psychopharmacologic therapy on heart rate variation. Nervenarzt 1995;66(9):678-685.

Rilea SL, Roskos-Ewoldsen B, Boles D. Sex differences in spatial ability: a lateralization of function approach. Brain and Cognition 2004;56(3):332-343.

Roberts JE, Bell MA. Two- and three-dimensional mental rotation tasks lead to different parietal laterality for men and women. Int J Psychophysiology 2003;50(3):235-246.

Ross ED, Orbelo DM, Cartwright J, Hansel S, Burgard M, Testa JA, Buck R. Affective-prosodic deficits in schizophrenia: comparison to patients with brain damage and relation to schizophrenic symptoms [corrected]. J Neurol Neurosurg Psychiatry 2001;70:597-604. Erratum in: J Neurol Neurosurg Psychiatry 2001;71:283.

Rossell SL, Bullmore ET, Williams SC, David AS. Sex differences in functional brain activation during a lexical visual field task. Brain and Language 2002;80(1):97-105.

Russell TA, Chu E, Phillips A pilot study to investigate the effectiveness of emotion recognition remediation in schizophrenia using the micro-expression training tool. ML. Br J Clin Psychol 2006;45(Pt 4):579-583.

Shaywitz BA, Shaywitz SE, Pugh KR, et al. Sex differences in the functional organization of the brain for language. Nature 1995;16;373(6515):607-609. Comment in: Nature 1995;16;373(6515):561-562.

Page 137: Schizophrenia and sex differences in emotional processing · Schizophrenia and processing of facial emotions: sex matters 27 Schizophrenia Research, 2005;78(1):61-67. Part Two: The

Chapter six 137

Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry 2001;50(9):651-658.

Shucard JL, Shucard DW, Cummins KR, Campos JJ. Auditory evoked potentials and sex-related differences in brain development. Brain and Language 1981;13:91-102.

Shucard JL, Shucard DW. Auditory evoked potentials and hand preference in 6-month-old infants: Possible gender-related difference in cerebral organisation. Developmental Psychology 1990;26:923-930.

Siegel-Hinson RI, McKeever WF. Hemispheric specialisation, spatial activity experience, and sex differences on tests of mental rotation ability. Laterality. 2002;7(1):59-74.

Speck O, Ernst T, Braun J, Koch C, Miller E, Chang L. Gender differences in the functional organization of the brain for working memory. Neuroreport 2000;3;11(11):2581-2585.

Spohn HE, Strauss ME. Relation of neuroleptic and anticholinergic medication to cognitive functions in schizophrenia. J Abnorm Psychol 1989;98(4):367-380.

Toichi M, Sugiura T, Murai T, Sengoku A. A new method of assessing cardiac autonomic function and its comparison with spectral analysis and coefficient of variation of R-R interval. J Auton Nerv Syst 1997;62(1-2):79-84.

Völlm BA, Taylor AN, Richardson P, Corcoran R, Stirling J, McKie S, Deakin JF,Elliott R. Neuronal correlates of theory of mind and empathy: a functional magneticresonance imaging study in a nonverbal task. Neuroimage 2006;29(1):90-98.

Weiss E, Siedentopf CM, Hofer A, et al. Sex differences in brain activation pattern during a visuospatial cognitive task: a functional magnetic resonance imaging study in healthy volunteers. Neuroscience Letters 2003;344(3):169-172.

Wise PM, Dubal DB, Rau SW, Brown CM, Suzuki S. Are estrogens protective or risk factors in brain injury and neurodegeneration? Reevaluation after the Women’s health initiative. Endocr Rev 2005;26(3):308-12.

Wolwer W, Frommann N, Halfmann S, Piaszek A, Streit M, Gaebel W. Remediation of impairments in facial affect recognition in schizophrenia: efficacy and specificity of a new training program. Schizophr Res 2005;80(2-3):295-303.

Wout M van ‘t, Aleman A, Bermond B, Kahn RS. No words for feelings: alexithymia in schizophrenia patients and first-degree relatives. Compr Psychiatry 2007;48(1):27-33.

Wright I, Rabe-Hesketh S, Woodruff P, David A, Murray R, Bullmore E. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000;157:16-25.

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138 General Discussion

Zahn TP, Carpenter WT Jr, McGlashan TH. Autonomic nervous system activity in acute schizophrenia: II. relationships to short-term prognosis and clinical state. Arch Gen Psychiatry 1981a;38(3):260-266.

Zahn TP, Carpenter WT Jr, McGlashan TH. Autonomic nervous system activity in acute schizophrenia: I. method and comparison with normal controls. Arch Gen Psychiatry 1981b;38(3):251-258.

Zahn TP, Jacobsen LK, Gordon CT, McKenna K, Frazier JA, Rapoport JL. Autonomic nervous system markers of psychopathology in childhood-onset schizophrenia. Arch Gen Psychiatry 1997;54(10):904-912.

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140 Nederlandse samenvatting

Nederlandse samenvattingDe dagelijkse klinische praktijk heeft geïnspireerd tot het schrijven van dit proef-schrift. Hoewel er tot een jaar of tien geleden nog weinig aandacht was voor sek-severschillen bij schizofrenie, liet het klinisch werk allerlei verschillen zien tussen mannelijke en vrouwelijke patiënten in bijvoorbeeld incidentie (lager bij vrouwen), premorbide functioneren (beter bij vrouwen), leeftijd waarop de eerste psycho-tische klachten zich manifesteren (later bij vrouwen), symptomatologie (minder negatieve symptomen bij vrouwen), co-morbiditeit (meer affectieve klachten bij vrouwen) en beloop (gunstiger bij vrouwen). Inmiddels is er op wetenschappe-lijk gebied meer belangstelling voor deze verschillen, enerzijds omdat deze meer informatie zouden kunnen verschaffen over het ziekteproces zelf, anderzijds om-dat ze aanleiding zouden kunnen geven tot verschillen in behandeling. Hoewel nog niet zeker is welke mechanismen ten grondslag liggen aan deze seksever-schillen, wordt in het algemeen aangenomen dat de invloed van geslachtshor-monen op het zich ontwikkelende brein hierbij een grote rol speelt. Oestrogenen zouden mogelijk een beschermende werking hebben door het bevorderen van de rijping en ontwikkeling van de hersenen en deze zo minder kwetsbaar maken voor invloeden van buiten. Daarnaast zouden verschillen in geslachtshormonen tussen mannen en vrouwen leiden tot verschillen in lateralisatie en specialisa-tie van hersengebieden, met als gevolg verschillen in vaardigheden. Voorbeel-den van sekseverschillen in functioneren op basis van seksueel dimorfisme van het brein zijn onder andere verschillen in prestaties op taaltaken (beter bij vrou-wen) en op visuo-spatiële taken (beter bij mannen). Ook emotieherkenning (in gezichtsuitdrukkingen en in taal) gaat vrouwen beter af dan mannen. Taalvaar-digheden en vaardigheden op het gebied van emotieherkenning zijn essentieel voor goed sociaal functioneren. Bij patiënten met schizofrenie zijn stoornissen vastgesteld in deze vaardigheden. Aangezien mannelijke patiënten sociaal min-der goed blijken te functioneren dan vrouwelijke patiënten, leek het zinvol om na te gaan in hoeverre de voorsprong die gezonde vrouwen hebben op verschil-lende vlakken van emotionele informatieverwerking behouden blijft bij schizo-frenie. Behoud van die voorsprong zou immers mede een verklaring kunnen zijn voor het feit dat vrouwelijke patiënten grotere sociale vaardigheden hebben dan mannelijke patiënten.

In dit proefschrift zijn daarom sekseverschillen onderzocht op een aantal ge-bieden van emotionele informatieverwerking, namelijk: emotieherkenning in ge-zichtsuitdrukking en taal; werkgeheugen bij simultane en sequentiële verwerking van emotie en taal; lange termijn geheugen voor visuele positieve, negatieve en neutrale informatie; neiging tot activatie/inhibitie; empathie en sociale cognitie.

In Hoofdstuk 1 (Inleiding) wordt een overzicht gegeven van bovengenoemde sekseverschillen bij schizofrenie. Verder wordt aangegeven waarom onderzoek naar sekseverschillen in emotionele informatieverwerking een goede invalshoek is om verschillen te bestuderen in de wijze waarop de ziekte zich manifesteert bij mannelijke en vrouwelijke patiënten met schizofrenie.

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Nederlandse samenvatting 141

Hoofdstuk 2 beschrijft sekseverschillen in emotieherkenning in gezichten en in gesproken taal.

De eerste taak, waarbij 6 emoties (bang, verdrietig, boos, walging, blij, ver-baasd) herkend moeten worden in mannen- en vrouwengezichten, laat zien dat vrouwen beter zijn in het herkennen van de negatieve emoties dan mannen. Hoewel patiënten het significant slechter doen dan controles blijft dit seksever-schil aanwezig bij de patiënten. Dat wil zeggen dat zieke mannen het het slechtst doen van alle groepen.

Een zelfde effect wordt gevonden bij de tweede emotieherkenningstaak, waar-bij 4 emoties (bang, boos, blij en verdrietig) herkend moeten worden in gespro-ken zinnen. Zowel in het herkennen van affectieve prosodie (de toon waarop iets gezegd wordt) als in het herkennen van de emotionele inhoud van een zin blij-ken vrouwen beter te zijn dan mannen. Dit effect blijft behouden bij patiënten, ondanks het feit dat alle patiënten het significant slechter doen dan de controles. Ook hier zijn het dus weer de zieke mannen die de laagste scores halen.

Omdat in andere studies gesuggereerd is dat cognitief verval mogelijk de be-langrijkste factor is bij het ontstaan van stoornissen in emotionele informatiever-werking van taal, is een aparte analyse gedaan met IQ (Raven) als co-variaat. Hieruit blijkt dat de gevonden sekse- en patiëntverschillen op de prosodie scores niet beïnvloed worden door IQ, maar dat de patiëntverschillen op de semantiek-scores verdwijnen na correctie voor IQ. Met andere woorden, de slechte scores van patiënten bij het herkennen van de emotionele inhoud van taal lijken vooral bepaald te worden door IQ (cognitief verval), terwijl de slechte scores op proso-die hiervan relatief onafhankelijk lijken te zijn.

Behalve naar herkenning van prosodie en semantiek is gekeken naar herken-ning van prosodie met interferentie van incongruente semantiek en vice versa. Alle deelnemers hadden de meeste moeite met herkennen van prosodie met af-leiding door affectief incongruente semantiek. Met name de zieke mannen kozen in deze conditie vaak de affectieve semantische betekenis (die eigenlijk gene-geerd moest worden). Na correctie voor IQ waren de controles niet meer signi-ficant beter dan de patiënten, maar deden de vrouwen het wel nog steeds beter dan de mannen.

Aangezien emotieherkenning cruciaal is voor sociaal functioneren, zouden deze resultaten mede kunnen verklaren waarom vrouwen met schizofrenie betere so-ciale vaardigheden hebben en behouden dan mannen met schizofrenie.

Ter contrastering is een visuele mentale rotatietaak afgenomen, een taak waar-van is aangetoond dat mannen hem over het algemeen significant beter doen dan vrouwen. Inderdaad wordt daarop een sekseverschil gevonden dat echter geheel is toe te schrijven aan de prestatie van de gezonde mannen, die significant be-ter scoren dan de andere 3 groepen. Zowel de gezonde vrouwen, als de manne-lijke en vrouwelijke patiënten scoren op hetzelfde niveau. Dat betekent dat zieke mannen significant slechter scoren dan gezonde mannen, terwijl zieke en gezon-de vrouwen geen verschil laten zien. Het oorspronkelijke sekseverschil op de ro-tatietaak blijft dus in dit geval niet bewaard bij schizofrenie.

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142 Nederlandse samenvatting

Verklaringen hiervoor zouden kunnen zijn dat lage oestrogeenspiegels bij vrou-welijke patiënten hun prestaties op de visuo-spatiële taak bevorderd hebben, of dat mannen en vrouwen verschillende strategieën gebruiken en verschillende her-sengebieden activeren bij het uitvoeren van deze taak. Zo zijn er aanwijzingen dat mannen meer rechts gelateraliseerd zijn bij het uitvoeren van visuo-spatië-le taken dan vrouwen. Aangezien schizofrenie geassocieerd is met disfunctie van de rechter hemisfeer zou dit voor mannen grotere gevolgen kunnen hebben voor de prestaties op deze taak dan voor vrouwen.

De studie in Hoofdstuk 3 onderzoekt sekseverschillen in het simultaan en se-quentieel verwerken van taal en emotie. Daartoe zijn 3 taken afgenomen.

Taak 1 is een simultane werkgeheugentaak (WG taak) waarbij tegelijkertijd een emotie moet worden herkend in een gezicht (keuze tussen boos of bang) en hardop moet worden geteld. Controles doen dit significant beter dan patiënten. Dit effect blijkt volledig gebaseerd te zijn op de slechte prestatie van de zieke mannen, aangezien de zieke vrouwen net zo goed scoren als de gezonde man-nen en vrouwen.

Een eenvoudige taak als deze simultane WG taak zal normaalgesproken geen overbelasting geven van het werkgeheugen en goed kunnen worden uitgevoerd. Wanneer de werkgeheugencapaciteit verminderd is, zoals bij schizofrenie, kan een simultane WG taak echter aanleiding geven tot overbelasting. Deze overbelas-ting is bij vrouwen mogelijk geringer omdat vrouwen in het algemeen beter zijn in emotieherkenning en daardoor minder werkgeheugencapaciteit nodig hebben. Een andere verklaring zou kunnen zijn dat mannen en vrouwen verschillende her-sengebieden activeren bij werkgeheugentaken. Zo zouden mannen meer R gela-teraliseerde of bilaterale activering laten zien bij verbale werkgeheugentaken en vrouwen meer L gelateraliseerde activering. Het tegelijkertijd uit moeten voeren van een R gelateraliseerde emotie- herkenningstaak zou zo bij mannen mogelijk meer interferentie geven en bij mannelijke patiënten (omdat het werkgeheugen gestoord is bij schizofrenie) kunnen leiden tot slechtere prestaties.

Bij taak 2 (sequentiële WG taak) moeten alle deelnemers achtereenvolgens in 3 subtaken een bepaalde opdracht uitvoeren (1) subtaak Rekenen: het uitrekenen van een eenvoudige som; (2) subtaak Gezichten: het identificeren van een ge-zicht als zijnde ‘mannelijk’ of ‘vrouwelijk’ en (3) subtaak Emoties: het herkennen van een emotie in een gezicht als ‘boos’ of ‘bang’. Deze informatie moeten ze in gedachten houden, vergelijken met een woord dat op het computerscherm ver-schijnt en aangeven of beide woorden op elkaar rijmen (bijvoorbeeld ‘zes-fles’; ‘man-kan’; ‘boos-roos’). Sekseverschillen worden op geen van deze subtaken vastgesteld. Patiënten doen het significant slechter dan controles op de subtaak Emoties, maar niet op de subtaak Rekenen en marginaal slechter op de subtaak Gezichten. Dit kan niet uitsluitend het gevolg geweest zijn van slechtere emo-tieherkenning, aangezien dezelfde emoties gebruikt worden als bij de simultane WG taak en vrouwelijke patiënten daarop niet slechter scoren dan gezonde con-troles. Mogelijk vereist het herkennen van gezichten en emoties meer aandacht en is het daarom moeilijker voor patiënten.

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Taak 3 bestaat uit het aanbieden van 72 IAPS plaatjes waarvan de inhoud po-sitief, negatief of neutraal is en die gevalideerd zijn op valentie. Na een uur wordt aan alle deelnemers gevraagd welke afbeeldingen ze denken te herkennen uit een batterij waarvan ze de helft niet eerder gezien hebben. Patiënten herkennen alle typen plaatjes significant slechter dan de controles, ongeacht de emotionele be-tekenis van de afbeelding; sekseverschillen worden niet gevonden. Vrouwelijke patiënten doen het dus net zo slecht als mannelijke op deze taak.

De resultaten van deze studie suggereren dat vrouwelijke patiënten minder gevoelig zijn voor interferentie bij het gelijktijdig verwerken van taal en emotie dan mannelijke patiënten, maar dat mannelijke en vrouwelijke patiënten even grote beperkingen hebben in de capaciteit van werkgeheugen en lange termijn geheugen voor opslag en bewerking van (emotionele) informatie.

In Hoofdstuk 4 wordt het concept van Gray geïntroduceerd met betrekking tot 2 motivationele systemen, het Behavioral Inhibition Systeem (BIS) en het Behavioral Activation System (BAS), die gevoeligheid voor straf en beloning reguleren. BIS en BAS worden verondersteld de intensiteit van respectievelijk terugtrekgedrag en toenaderingsgedrag te reguleren in reactie op tekenen van dreiging of belo-ning uit de omgeving. BIS scores zouden gerelateerd zijn aan internaliserend ge-drag en gemiddeld hoger zijn bij vrouwen, BAS scores zouden gerelateerd zijn aan externaliserend gedrag en hoger bij mannen.

Verstoring in balans van BIS/BAS is gerapporteerd bij verschillende soorten psychopathologie. Zo zijn hoge BIS scores gevonden bij angst- en stemmings-klachten en hoge BAS scores bij manie en psychopathie. Bij schizofrenie zijn BIS/BAS scores nooit eerder bestudeerd. Omdat verondersteld wordt dat gevoelig-heid voor stress een pathway zou kunnen zijn voor het ontwikkelen van psycho-se, is het interessant om de scores van patiënten met schizofrenie op de BIS/BAS vragenlijsten in kaart te brengen en te vergelijken met die van gematchte con-troles. Daarnaast is gekeken naar de relatie tussen BIS/BAS scores, psychopa-thologie en fysiologische maten.

Patiënten blijken significant hoger te scoren op de BIS. Het sekseverschil (ho-gere BIS scores bij vrouwen) verdwijnt wanneer gecorrigeerd wordt voor ziekte-duur (langer bij de vrouwen). Hoge scores op de BIS correleren met ziekteduur en met lage scores op de negatieve symptomen van de PANSS.

Op de BAS worden geen significante verschillen gevonden tussen patiënten en controles, mogelijk mede tengevolge van medicatiegebruik, aangezien antipsy-chotica invloed hebben op dopamine spiegels en dus op het reward systeem.

Naast de BIS/BAS scores zijn gemiddelde Hartslagfrequentie (Heart Rate; HR) en hartslagvariabiliteit (Heart Rate Variability; HRV) gemeten. Patiënten laten een significant hogere HR en lagere HRV zien dan controles, maar deze bevinding blijkt geheel op rekening te komen van de hartwaarden bij patiënten die cloza-pine gebruiken. Een correlatie tussen BIS/BAS waarden en fysiologische maten wordt niet aangetoond. Dit zou kunnen betekenen dat BIS/BAS scores meer een trait dan een state waarde vertegenwoordigen.

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De belangrijkste conclusie is dat zowel mannelijke als vrouwelijke patiën-ten met schizofrenie meer gevoelig zijn voor dreiging dan controles. Dit bete-kent dat ze mogelijk meer risico lopen om stimuli negatief in te schatten. Of dit mede oorzaak of gevolg is van psychotische klachten zal nader onderzoek moe-ten uitmaken. In ieder geval zou het risico op nieuwe psychoses hierdoor ver-hoogd kunnen worden.

In Hoofdstuk 5 wordt gekeken naar sekseverschillen in empathie en in perceptie van sociale interactie bij patiënten met schizofrenie. Verschillende studies heb-ben aangetoond dat vrouwen empathischer zijn dan mannen en dat het vermo-gen tot empathie verminderd is bij patiënten met ontwikkelingsstoornissen zoals schizofrenie en autisme. Aangezien het vermogen je in te leven in de gevoelens en gedachten van anderen essentieel is in het sociale contact, kan vermindering hiervan aanleiding geven tot belemmeringen in het sociaal functioneren. De stu-die is uitgevoerd met behulp van de vragenlijsten van Baron-Cohen, die de mate van empathiseren en systematiseren in kaart brengen, en een nieuw ontwikkel-de taak voor sociale cognitie. Zoals verwacht blijken vrouwen hoger te scoren op de empathielijst dan mannen en controles hoger dan patiënten. Het seksever-schil blijft bewaard bij schizofrenie, wat betekent dat mannelijke patiënten het laagst scoren van alle groepen. Op de systematieklijst scoren de mannen hoger dan de vrouwen, maar verschillen controles niet van patiënten. Hierin verschil-len patiënten met schizofrenie dus van patiënten met autisme, die hoger scoren op de systematieklijst dan gezonde mensen.

Omdat patiënten met schizofrenie bekend zijn met stoornissen in taal en emotieherkenning, en deze stoornissen de prestaties op een sociale interactie perceptietaak kunnen beïnvloeden, werd een taak ontwikkeld waarin taal en emo-tieherkenning geen rol spelen. In het eerste deel van deze taak krijgen alle deel-nemers 15 plaatjes met 2 getekende figuurtjes te zien, van wie de één (figuur A) de proefpersoon zelf moet voorstellen die in gesprek is met de ander (figuur B). Bij elk plaatje moeten de deelnemers inschatten hoe vervelend B het vindt om met A contact te hebben. Patiënten met schizofrenie blijken deze sociale situa-ties structureel als minder vervelend voor de ander in te schatten dan controles. Mannen schatten de situatie ook als minder vervelend in dan vrouwen.

In het tweede deel van de taak worden 11 sets van 2 plaatjes getoond, met in elk plaatje 2 getekende figuurtjes in een gelijksoortige situatie. De plaatjes ver-schillen echter in lichaamshouding van de figuurtjes of in afstand van de figuurtjes tot elkaar. Bij deze taak moet worden aangegeven in welk van de 2 plaatjes het ene figuurtje (B) het leuker vindt om met het andere figuurtje (zijnde de proef-persoon A) te praten. Hierin worden geen verschillen gevonden tussen patiënten en controles of tussen mannen en vrouwen. Kennelijk is het voor patiënten geen probleem de meest plezierige interactie te kiezen uit 2 interacties, maar is het moeilijker om een waardeoordeel te geven over een sociale interactie op basis van tamelijk abstracte informatie (lichaamstaal). Hoge scores op empathisch vermo-gen blijken te correleren met hoge scores op de eerste sociale cognitie taak. Sa-menvattend laten de resultaten van deze studie zien dat controles empathischer

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zijn dan patiënten en dat vrouwen empathischer zijn dan mannen; het sekse-verschil in empathie blijft behouden in de ziekte. Verder zijn vrouwen gevoeliger voor subtiele negatieve signalen in de lichaamshouding van de gesprekspartner dan mannen en geldt datzelfde voor controles t.o.v. patiënten.

In Hoofdstuk 6 worden de belangrijkste bevindingen samengevat en bespro-ken welke implicaties deze hebben voor een beter begrip van sekseverschillen bij schizofrenie en voor een meer seksespecifieke behandeling van patiënten met schizofrenie.

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DankwoordIn de eerste plaats wil ik mijn promotoren prof. dr. René Kahn en prof. dr. André Aleman en mijn co-promotor dr. Jack van Honk bedanken, die altijd weer in staat bleken alle grote en kleine problemen die zich aandienden effectief te couperen.

René, je toonde je meteen enthousiast toen ik je voorstelde om emotieonder-zoek te gaan doen bij patiënten met schizofrenie en daarbij te kijken naar sekse-verschillen. Dank je wel voor de ruimte die je me daarvoor hebt geboden.

André, jij was onvermoeibaar in het aandragen van nieuwe ideeën, artikelen en onderzoeksmethoden. Soms dreigde je in je enthousiasme wel eens te ver-geten dat er ontelbaar veel patiënten nodig zouden zijn om al die ideeën daad-werkelijk om te zetten in onderzoek. Maar meestal werkte jouw benadering heel stimulerend.

Jack, het was een hele ervaring kennis te maken met jouw onorthodoxe ma-nier van onderzoek doen. Buiten de kaders denken is jouw handelsmerk en dat is onmisbaar voor vernieuwend onderzoek. Dank voor je begeleiding.

Alle patiënten en gezonde controles komt veel dank toe vanwege de opge-wekte en onverstoorbare wijze waarop ze steeds weer bereid waren zich over te geven aan alle testen.

Daarnaast wil ik graag iedereen bedanken die geholpen heeft bij de prakti-sche uitvoering van het onderzoek. Erno Hermans, jij was vaak mijn grote steun en toeverlaat bij ingewikkelde technische zaken. Menig keer hebben we mid-den in testsessies een beroep op je gedaan om problemen in de apparatuur te verhelpen.

Yvette van Dokkum en Myra van Leeuwen: jullie hebben me heel veel werk uit handen genomen bij het testen en het verwerken van de gegevens. Zonder jullie hulp zou het onderzoek vast veel langer geduurd hebben. Matthijs Vink, wonder van statistiek en techniek: 1 kleine aanwijzing van jou scheelde me vaak dagen werk, dank je wel. Sophie van Rijn, Daan Baas en vooral Mascha van ‘t Wout van de Impulsgroep Emotie onderzoek: bedankt voor alle hulp en inspiratie. Esther Caspers: met zoveel onderzoekers zijn geschikte deelnemers voor het onderzoek nauwelijks meer te vinden, bedankt voor je hulp daarbij.

Mijn directe collega-psychiaters van de zorglijn, Wiepke Cahn, Nicoletta van Veelen en natuurlijk mijn directe maatje Jean-Paul Selten wil ik graag bedanken voor de samenwerking, de steun en de waarneming van al het schrijfverlof.

Voor de morele steun, de fantastische samenwerking en de gezelligheid wil ik graag alle andere collega’s bedanken: de verpleegkundigen, de vaktherapeuten, de dames van het secretariaat, de collega’s van de andere zorglijnen. Jullie zorg-den voor de broodnodige afleiding bij het eenzame onderzoeksgeploeter.

Alle arts-assistenten psychiatrie van het UMC wil ik speciaal bedanken voor de leuke samenwerking en hun grote inzet. Dat maakte de begeleiding tot een mak-kelijke en plezierige taak en de patiëntgebonden werkzaamheden relatief licht. De gezelligheid en de goede tips heb ik bovendien zeer gewaardeerd.

Dankwoord

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Mijn nieuwe collega’s en paranimfen Simone Kool en Cecile Gijsbers van Wijk ben ik veel dank verschuldigd voor hun hulp in de laatste weken voor de pro-motie.

Verder wil ik ook vooral al mijn vrienden bedanken die mij telkens vroegen waar ik in ’s hemelsnaam aan begonnen was op mijn leeftijd. Dat stimuleer-de mij altijd bijzonder, omdat ik dan zeker wist dat ik het helemaal voor mezelf deed, gewoon omdat ik het leuk vond. Mijn moeder en mijn broer ben ik dank-baar voor het vertrouwen dat ze hadden dat ik ook deze onderneming wel weer tot een goed einde zou brengen.

Mijn gezin tenslotte wist altijd mijn werkzaamheden te relativeren, door zoveel dingen aan te dragen die mijn onmiddellijke aandacht opeisten, dat mijn onder-zoek daar alleen maar bleekjes bij af kon steken en promoveren bijzaak bleef.

Dankwoord

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Curriculum VitaeMarion Scholten werd op 4 maart 1954 geboren te Palembang, Indonesië. In juni 1972 werd het diploma gymnasium beta behaald aan het Gymnasium Felisenum te Velsen-Zuid. Een jaar later behaalde zij de propedeuse Psycholo-gie aan de Universiteit van Amsterdam, waarna zij aan dezelfde universiteit Ge-neeskunde studeerde (1973-1982). Na een assistentschap in de psychiatrie in het Christelijk Sanatorium te Zeist, specialiseerde zij zich tot psychiater in PMS Vijverdal en St. Annadal te Maastricht (1983-1986). De keuzestages werden res-pectievelijk bij de GGD-rijdienst en RIAGG-ZNW in Amsterdam en in het Pieter Baan Centrum in Utrecht gedaan. April 1987 werd zij ingeschreven in het spe-cialisten-register. Naast de opleiding tot psychiater volgde zij in Maastricht van 1983 tot 1986 de IMP-opleiding psychotherapie (gezinstherapie, psychodynami-sche psychotherapie en gedragstherapie) en in Amsterdam de opleiding groeps-therapie (1986-1987).

Na de opleiding ging zij werken als psychiater in het toenmalige Provinciaal Ziekenhuis te Santpoort en had daarnaast een eigen praktijk voor psychotherapie. In het kader van alle veranderingen in de zorg voor psychiatrische patiënten in Amsterdam, gaf zij in 1988 leiding aan de open afdeling van het Sociaal Psychia-trisch Dienstencentrum Centrum/Oud-West en ontwierp zij daarvoor een deel van de behandel-programma’s. Van oktober 1989 tot april 2000 was zij werkzaam in de Valeriuskliniek in Amsterdam als hoofd van de open vervolgafdelingen. Daar-naast zette zij poliklinisch een behandeling op voor patiënten met eetstoornissen, in samenwerking met de RIAGG-ZNW en de diabetesafdeling van de VU. Vanaf april 2000 tot januari 2007 was zij verbonden aan het UMC te Utrecht als psychi-ater-docent-onderzoeker op de zorglijn Psychotische stoornissen van de afdeling Volwassenenpsychiatrie, Divisie Hersenen. Met ingang van 01-01-2007 heeft zij een functie aanvaard als Directeur Zorg bij Mentrum in Amsterdam.

Bestuurlijk is zij actief geweest als bestuurslid van de Nederlandse Vereni-ging van Vrouwelijke Artsen, regio Amsterdam (VNVA; 1986-1990), als voorzit-ter van de sectie Vrouwen In de Psychiatrie (VIP;1996-2000) en als bestuurslid van de Nederlandse Vereniging voor Psychiatrie (NVvP, portefeuille Public Rela-tions; 1999-2003). Daarnaast maakte zij van 2001 tot 2004 deel uit van de re-dactieraad van het tijdschrift De Psychiater.

Curriculum Vitae

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