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Gender Differences In Schizophrenia

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Schizophrenia is a recurring disorder and is defined by abnormal in five areas in general, including hallucinations, delusions, disorganized things, disorganized or abnormal motor behavior, and negative symptoms (APA, 2013; McNally & McCarley, 2016). However, would there be any differences between males and females in terms of age-at-onset for the first episode and symptoms? Are there any reasons behind those differences?

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To begin with, males and females are experiencing different rates of incidence and prevalence, age-at-onset for the first episode and diagnostic issues (Abel, Drake, & Goldstein, 2010; Aleman, Kahn, & Selten, 2003; APA, 2013; McGrath, J., Saha, S., Chant, & Welham, 2008). For the rates of incidence and prevalence, although there are similar prevalence of schizophrenia among males and females, the onset of female is a few years later than male (Angermeyer & Kühn, 1988; Jones, 2013; Kirkbride et al., 2012; ,Li, Ma, Wang, Yang, & Wang, 2018; Nowrouzi et al., 2015). Besides, there would be multiple incidence of schizophrenia onset peaks for both males and females across the lifetime. For males, early twenties would be the highest incidence onset frequency and second peak would be in the mid-thirties; for females, the pattern of peaks is similar to males, on the other hand, the third peak occurs in the early sixties (Abel et al., 2010; Drake, Addington, Viswanathan, Lewis, Cotter, Yung, & Abel, 2016). Besides, comparing between males and females, males would be higher rate of onset from the first two peaks, however, females would be higher frequency rates of onset in late middle age which described as the third peak. In terms of prevalence of schizophrenia, according to American Psychiatric Association (2013), the rates of schizophrenia as a lifetime developing disorder is approximately 0.3% to 0.7%. However, no gender differences shows in terms of prevalence (McGrath, Saha, Chant, & Welham, 2008).

Moreover, studies of differences in age-of-onset are the most stimulating into account of the gender differences in schizophrenia. Males develop schizophrenia at the age between 18 and 25; while females develop schizophrenia with the mean age between 25 and 35. Thus, the age-of-onset distribution for males and females are considered as non-isomorphic, in the other words, the distribution is not the same or similar. As discussed before, females seem to have the third peaks in the age-of-onset of schizophrenia, i.e. the third major prevalence of females in late middle age. This could be understood by reduction of estrogens after menopause which would be discussed later on (Ochoa, Usall, Cobo, Labad, & Kulkarni, 2012).

Besides the incidence and prevalence of schizophrenia, differences also shown in terms of symptoms presentation. According to Li and his colleagues (2016), differences in symptoms shows in positive, negative and cognitive symptoms. For males, more negative symptoms would be appear for males with schizophrenia and more server clinical features comparing to females with schizophrenia, including social withdrawal, substance abuse and undermine or contradictory emotional issue. On the other hand, females with schizophrenia would often showing more in mood disturbance as well as the affective symptoms, for instance, depressive symptoms. Besides, while comparing between males and females, males are more presenting negative symptoms, violent behavior and disorganized, while females are showing more depression and social anxiety (Li et al.,2016; Riecher-Rössler, Butler, & Kulkarni, 2018). Apart from the positive and negative symptoms, males also reported to be more serious cognitive deficit them females, including immediate and delayed memory (Li et al., 2016). However, there is no gender different in cognitive deficit in terms of language, visuospatial and attention. With the higher risk for schizophrenia in males, males with schizophrenia is generally first perceived negative and cognitive symptoms. On the other hand, females with schizophrenia is generally first to record positive and affective symptoms.

To order to understand the reasons behinds those differences, I would like to separate two main factors, biological, and social and environmental factors. Biological factors are about the brain structure, hormone hypothesis and sex chromosome hypotheses; on the other hand, social and environmental factors are about the social functioning and substance abuse.

In terms of biological factors, differences of brain structure could explain the differences between gender. Some studies suggested that schizophrenia, although it is not considered as the category of neurodevelopmental disorder in DSM-V by APA (2013), is related to fetal and early postnatal origins (Abel et al., 2010; Goldstein & Walder, 2006). It is believed that gender differences in brain abnormalities in schizophrenia are proposed at the early period of sexual differentiation of the brain, i.e. fetal and early postnatal development. For males with schizophrenia, in the understanding of the gender different about the brain structural abnormalities of schizophrenia, there are greater abnormalities than females with schizophrenia (Abel et al., 2010; Nopoulos, Flaum, & Andreasen, 1997). Under MRI study and post-mortem study, males with schizophrenia reported to be larger lateral and third ventricles, which functioned as filling of cerebrospinal fluid and protection of brain (Saladin, 2004), and anterior temporal horn; smaller medial temporal volumes, for instance, hippocampus, which responsible for retrieval condition including recall of episodic, semantic, and autobiographical information (Banich & Compton, 2011); amygdala, which plays an important role in affective information and emotional expression (Banich & Compton, 2011); Herschl’s gyrus, a primary auditory cortex; superior temporal gyrus which also contains auditory cortex responsible for processing sounds (Bigler et al., 2007); and overall smaller volume in frontal and temporal lobe (Abel et al., 2010). Besides, abnormalities of left-lateralized also reported in males with schizophrenia rather than females. More general brain destruction show in males than females with schizophrenia about the greater sulcal volume and smaller thalamic size in which the thalamic size is considered to be positively associated with the volume of frontal and temporal lobe (Brickman et al., 2004). Smaller volume of superior temporal gyrus, the site of auditory association cortex, also found in males with schizophrenia. On the other hand, there are also some abnormality in females with schizophrenia in terms of the brain structure comparing with males with schizophrenia. Volume of heteromodal association areas, which mainly focus on integrating sensory data, motor feedback, and promote learning and creates thought, expression, and behavior, is smaller among females with schizophrenia than males including dorsolateral prefrontal cortex, superior temporal gyrus and orbital prefrontal cortex (Abel et al., 2010; Buchanan et al., 2004; Narr et al., 2004). However, in terms of cognitive symptoms, similar abnormalities are reported in dorsolateral prefrontal cortex, which responsible for executive functioning, for instance, decision making, working memory, social cognition, and neurotransmitter functioning, for both males and females with schizophrenia (Abel et al.,2010; Phan, Quo, & Wang, 2006). On the other hand, short-term and long-term memory deficits is more likely to be contributed to males with schizophrenia instead of females (Han et al., 2012).

Besides the influence of difference brain structure, hormone hypotheses also suggest a way to explain the difference between males and females with schizophrenia in terms of schizophrenia symptoms and age-of-onset. Gender differences in schizophrenia involve gonadal hormones (Li et al. 2016). Estrogen, for instance, act a possible roles in protecting from and against schizophrenia pathology in females. In the other words, the late age-of-onset and the incidence peak around late middle age, so-called menopausal age, of female are supporting the estrogen hypothesis. During menopausal age of female, lack of estrogen show a high relationship with the severity of psychotic symptoms including schizophrenia symptoms (Grigoriadis & Seeman, 2002; Li et al., 2016). For instance, in Grigoriadis and Seeman’s study in 2002, the female with schizophrenia were having a more severe schizophrenia symptoms during menstrual cycle with low estrogen phase. On the other hand, in the case of males with schizophrenia, there is a negative correlation between plasma estrogen level and schizophrenia symptoms. Besides the estrogen, the primary female sex hormone, testosterone, a major male hormone, also act an influences in schizophrenia in terms of the symptoms (Ko et al., 2007; Lo et al. 2016). There is an association with a negative correlation between levels of testosterone and the severity of schizophrenia symptoms. Low level of testosterone and serum testosterone level often associated with greater severity of negative symptoms of patient with schizophrenia (Sisek-Šprem, Križaj, Jukić, Milošević, Petrović, & Herceg, 2015). Not only gender hormone, estrogen and testosterone, presenting the influence to the schizophrenia, oxytocin also influence the symptoms of schizophrenia. Oxytocin is a hormone generally produced in the hypothalamus and released by the posterior pituitary (Standring, 2015). Oxytocin plays a role of reproductive function (Li et al., 2016; Yang, Wang, Han, & Wang, 2013). In males or females with schizophrenia, oxytocin level may elevate the psychotic symptoms (Lee, Macbeth, Pagani, & Young, 2009). Sensorimotor gating by the prepulse inhibition of the startle reflex which reducing the intense sensory stimuli of the sudden, in other words, weakening the sensory stimulus. This sensorimotor gating is so-called an attentional mechanism to reduce the distract stimuli. For a deficit in the sensorimotor gating would generate feature of schizophrenia symptoms. It was also reported that males and females with schizophrenia with higher level of oxytocin would develop fewer schizophrenia symptoms with improved cognitive (Cochran et al, 2013; Li et al., 2016). As a result, regulating central dopamine and hence performing antipsychotic effect would be believed as the function oxytocin in terms of schizophrenia.

Besides, the dopaminergic system also explain part of the gender differences in terms of schizophrenia. Different activity level of neurotransmitter and receptors reflecting on different positive and negative schizophrenia symptoms. Abnormalities in dopaminergic system is shown in both males and females with schizophrenia (Banich & Compton, 2011; Kesby, Eyles, McGrath, & Scott, 2018; Li et al. 2016). In general, there would be two main families of receptors, i.e. D1-like, which increase the production of cyclic AMP, a second-messenger, and located on postsynaptic sites; and D2-like, which decrease the production of cyclic AMP and located on both postsynaptic and presynaptic sites (Banich & Compton, 2011). For males and females with schizophrenia, increased subcortical synaptic dopamine content and basal dopamine synthesis capacity were found (Bloemen et al., 2013; Egerton et al., 2013). Besides, positive symptoms were found to be related with the increased subcortical dopamine synthesis (Banich & Compton, 2011). Dopaminergic neurotransmission is also related to inflect attention, effectiveness of executive functioning and positive affect in which differences between males and females in terms of dopaminergic system also shown (Riccardi, Park, Anderson, Doop, Ansari, Schmidt, & Baldwin, 2011). For females, in terms of cognitive functioning, higher baseline extracellular levels of dopamine release is recorded with higher d-amphetamine which induced dopamine release ; meanwhile, positive affect had found correlating with dopamine release in substantia nigra which mediating dopaminergic function with affect (Riccardi et al., 2011).

Apart from the above, sex chromosome hypotheses also proposed to explain the gender difference among schizophrenia. In order to understand the gender differences, sex chromosomes, i.e. XX and XY, may be a role to investigate in the effect of neurodevelopment and sharing the sex-specific cognitive function (Bache & DeLisi, 2018; Li et al., 2016). Via the sex chromosome hypotheses, genetic predilection of schizophrenia could be considered with abnormal X chromosome and exuberance of schizophrenia have shown in Klinefelter’s males i.e. XXY and triple X females (Bache & DeLisi, 2018). With this abnormal number of X-chromosome, it is suggested that incidence in motor impairment and psychosis symptoms would be higher than normal populations (Hong & Reiss, 2014; Li et al., 2016). In the other words, higher prevalence of psychosis would be shown in person with excess sex chromosome. Besides the abnormal X chromosome of males and females with schizophrenia, there are some other chromosome-related fact which could explain the differences among them. For instance, G/G genotype of the catechol-O-methyltransferase (COMT) gene on chromosome 22q11, CAA and TATC polymorphism of the Nogo gene, and GPR50 gene on chromosome Xq28 were associated with females with schizophrenia only (Goldstein et al., 2013; Shifman et al.,2002; Tan et al., 2005; Thomson et al., 2005). One the other hand, chromosome 8p22 and chromosome 17p11.2-q25.1 were reported as abnormal only in males with schizophrenia (Williams et al., 2003; Xie et al., 2011).

On the other hand, apart from biological factors, social and environmental factors may also take into account of the gender differences. Environmental factors may shows a significant role in explain the hidden pathophysiology of schizophrenia. For instance, the infections, nutritional deficits and neurotoxins are influencing the brain development and causes of psychotic disorder (Brown, 2011). Substance abuse would also be understood as one of the environmental factors. Relationship is shown between psychosis symptoms and substance misuse in which the rates are higher in the first-episode psychosis patients (Stilo, Di Forti, & Murray, 2011). Although not all addictive drugs found to have ability in inducing psychotic symptoms, repeated use of stimulants, for instance cocaine and amphetamine, would activate the sensitization of dopamine system. In the other words, the dopamine system would be dysregulated and lead to develop psychotic symptoms. as discussed before, gender difference was shown in terms of dopaminergic system, different severity of the symptoms would be considered (Riccardi et al., 2011). Besides, the use of cannabis also found to be correlated with the increasing levels of psychotic symptoms. In the other words, cannabis would considered as one of the risk factors for psychotic disorder. Use of cannabis would increase the risk of development in later psychotic symptoms or disorders regards of psychosis awareness. age-of-onset of psychotic disorder for the cannabis user would be earlier than those nonusers (Stilo, Di Forti, & Murray, 2011). Early use of cannabis also reported to be correlated to impeded cortical maturation in males with high risk of schizophrenia development and probably increase the rate of disorder development. In early adolescence, males was found to be more heavily relying cannabis when compare to females, and thus to be at risk in schizophrenia development (French et al., 2015). The differences might also be explained in terms of the testosterone level in early adolescence, in which testosterone production would be related to aggressive norm-violating behavior and thus, drug use (Tarter et al., 2009). Besides, in the social factors or psychosocial factors, the social functioning would also generating the gender differences in schizophrenia. Females with schizophrenia shows had a better social functioning when comparing to males with schizophrenia as females reported a better social support while males would have more criticize than females. Males with schizophrenia also report to present greater social isolation and social withdrawal comparing with females with schizophrenia (Barajas, Ochoa, Obiols, & Lalucat-Jo, 2015; Gogos, Ney, Seymour, Van Rheenen, & Felmingham, 2019). Besides, stress and trauma also consider as one of the social factors. Traumatic life events seems to increase the risk of developing schizophrenia and affecting the severity of schizophrenia symptoms, for instance different kinds of abuse and childhood experience. Some studies were reported than females with schizophrenia have a history of traumatic event more frequent than males with schizophrenia, in which females report a greater risk of schizophrenia after traumatic event when comparing to males. Besides, with childhood abuse would also reported in females with schizophrenia and presenting more schizophrenia symptoms and depressive symptoms but not for males (Riecher-Rössler, Butler, & Kulkarni, 2018). For stress handling, females with schizophrenia was report to be greater emotional reactivity for daily stress which may also influence by the estradiol levels.

All in all, gender difference is shown in the schizophrenia development in terms of age-of-onset, and the symptoms development. The different in incidence rate and prevalence rates always reported in gender different of schizophrenia. Different in age-of-onset also reported for earlier in males and later in females, and females would have another peak for the late middle age. Differences also shown in schizophrenia symptoms between males and females with schizophrenia, i.e. males with schizophrenia would have higher tendency in suffering negative symptoms while females would be more chances in suffering positive symptoms instead. These differences could be explained in terms of biological and social factors. By the understanding of brain structure, hormones and chromosome, differences in the age-of-onset and symptoms presentation could be explained the gender difference. Besides, social factors, for instance the social structure or substance abuse, could also explain the gender differences. With the help among biological factors and social factors, it would be easier and clearer in understand the reasons behind the gender differences in age-of-onset and symptoms presentation. In order to have a full picture of understanding the causes of schizophrenia, with the help of many others perspective related to the explanation of gender differences, risk factors and protective factors would be useful in prevention, assessing and intervening schizophrenia with targeting in different gender.

31 August 2020

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