Schizophrenia Overview Though dependent on age group, the

Schizophrenia is a severe psychiatric disorder that is classified
within the broader category of psychosis. Hanlon et al., (2017) cites that
approximately 2% of the population is affected by psychosis and nearly 1% of
that is affected specifically by schizophrenia (Wu, Hill, Gogos, & Buuse, 2013). Schizophrenia is a complex
disorder and patients suffer a variable set of symptoms that occur as a
syndrome of positive symptoms, negative symptoms, and cognitive deficits. It
has been shown that schizophrenia is a combination of both genetic and
environmental factors (Wu et al., 2013). Both genders are greatly affected by
schizophrenia, however, gender differences have been documented in the clinical
presentation, course of illness, and responses to pharmacological and
psychosocial treatments.

            Gender differences
have been studied extensively in recent years, and though some definite
findings have been established, much is still up for debate. After providing an overview of
schizophrenia’s most understood gender differences, this paper will summarize
some relevant research done on the role of physiological factors in
schizophrenia and its gender differences. Specifically, these factors include
dopaminergic dysfunction, neuro-steroids, estrogen and brain-derived
neurotrophic factor (BDNF). A greater understanding of these physiological
gender differences will help in designing a more effective treatment, and avenues
for further research and development will be discussed.

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An Overview

            Though dependent on age group, the
genetic susceptibilities would explain why schizophrenia has a higher incidence
in men, compared to women (Hill, 2015). Men experience a peak age of onset that
is younger than women, occurring between the ages of 15 to 24 years. Whereas,
women experience a peak age of onset between 20 to 29 years, and then again
after the age of 45 (Hill, 2015, p. 42).

            In
general, men suffering from schizophrenia experience more cognitive dysfunction
and negative symptoms, which include apathy, social withdrawal, alogia, and lack
of motivation (Huang et al., 2017). Specifically, men have been found to
perform more poorly on attention, language, and executive functioning tasks
(Hill, 2015). In contrast, women tend to suffer more from positive symptoms
including hallucinations and persecutory delusions (Hill, 2015).

            Overall,
the prognosis of schizophrenia is worse for men than women (Hanlon et al.,
2017). Women were found to have better remission, less relapses, and were more
likely to benefit from better marital and housing situations, which may help
alleviate some symptoms of schizophrenia (Hanlon et al., 2017).

Dopaminergic
Dysfunction

            As
will be seen, dopamine is a major contributing factor to the development of
schizophrenia. Therefore, it is beneficial to highlight specific gender
differences in relation to dopaminergic systems, as these systems are also affected
by the remainder of the physiological factors.

One sex-specific characteristic that was found, was the role of catechol-O-methyl-transferase
(COMT), which metabolizes dopamine (Hill, 2015). Simply, a polymorphism in a
single nucleotide in the human COMT gene at codon 158 of Valine to Methionine
has been linked to reduced COMT enzymatic activity, and thus, schizophrenia (Witte
& Flöel, 2012; Hill, 2015). Interestingly, Risbrough, Ji, Hauger, &
Zhou (2014) developed the first “‘humanized'” COMT mouse model by inserting
COMT 158Met alleles into the mouse genome. Risbrough et al. (2014) tested the mice
who were Val/Val versus Met/Met, and found that male Val/Val mice were more
deficient in pre-pulse inhibition (PPI) and the opposite was true in female
mice. However, Met/Met female mice were more likely to experience fear
potentiated memory difficulties (Risbrough et al., 2014).

In Hill’s (2015) studies with mice it was found that males expressed 17%
more COMT activity in the prefrontal cortex, but also showed higher levels of
COMT dysfunction in the frontal cortex. Likewise, Gogos et al., (1998) found a
similar increase in dopamine levels of male frontal cortexes. Male mice showed
increased levels of aggression, and their performance on medial prefrontal
cortex (MPFC)-dependent visuospatial learning tasks were deficient (Papaleo et
al., 2008; Gogos et al., 1998). It has also been established that cognitive
function was more impaired in male COMT knockout mice compared to females, with
stress playing a factor as a sex x genotype x environment interaction (Papaleo
et al., 2012). Whereas, female mice deficient in COMT were only shown to
express impaired emotional reactivity (Gogos et al., 1998).

Overall, mice lacking the dopamine transporter showed increased levels of
dopamine, impaired PPI, and hyperactivity (Hill, 2015). However, studies on the
role of elevated dopamine levels show that males are more vulnerable to changes
in dopaminergic signaling. Specifically, males showed a greater deficit in PPI,
and this may be because female models have been shown to have more efficient
recovery and packaging of extracellular dopamine. Though dependent on specific
types of mutation and cognitive tasks, males also tended to show a greater
detriment in cognitive phenotype (Hill, 2015).

Neurosteroids

            Neurosteroids
naturally occur due to steroid-producing endocrine glands or they can be built
in the central nervous system from precursors of sterols (Baulieu & Robel,
1998). Dehydroepiandrosterone (DHEA) and DHEA-S – its sulfate ester – are among
the most common forms of neurosteroids available in the body (Huang et al.,
2017). Baulieu and Robel (1998) have indicated that DHEA and DHEA-S regulate
the receptors of neurotransmitters, including those of the dopamine system.
Therefore, with less DHEA or DHEA-S present, individuals are susceptible to
dysfunctions in dopaminergic signaling – a previously established schizophrenia
factor. Researchers have also established that neurosteroids play a role in
stress, mood stability, and aggression (Compagnone & Mellon, 1998). With
decreased levels of these neurosteroids, an individual may have reduced
neuroprotection, especially when exposed to other stressors. Thus, disturbances
in DHEA and DHEA-S levels play a role in various psychiatric illnesses, like
schizophrenia.

            Though,
DHEA and it sulfate ester function differently, Huang et al. (2017) established
that neurosteroids, in general, exert sex-specific effects. In their
discussion, Huang et al. (2017) state that an early onset of schizophrenia is
associated with lower levels of DHEA and DHEA-S, but only in males.
Specifically, lower levels of DHEA may make men more susceptible to the
development of schizophrenia, because they may require more DHEA just to
maintain brain development and stability, when compared to women (Huang et al.,
2017). Since the effects of schizophrenia, in relation to DHEA and DHEA-S, were
only seen in males, it can be assumed that these neurosteroids could be used as
a potential influencer and marker of the disease, but only in men.

Estrogen and
Brain-Derived Neurotrophic Factor

            As
will be illustrated, the role of estrogen, brain-derived neurotrophic factor
(BDNF), and their interaction, pose another deficit to men in the onset and
progression of schizophrenia. Estrogen itself is a naturally occurring, sex
steroid found predominantly in females. Interestingly, the effects of estrogen
modulate many neurotransmitter systems, including dopaminergic pathways (Wu et
al., 2013). For example, they can exhibit post-synaptic anti-dopaminergic
effects (Sanchez ? 2010). Moreover, Wu et al. (2013), state that many studies
have established neuroprotective effects exerted by estrogens, and these same authors
postulate that estrogens contribute to sex differences in psychiatric
disorders, such as schizophrenia.

            This
fact is illustrated by varying ages of schizophrenia onset between men and
women. Intuitively, because men have lower levels of estrogen, they are less
protected from its benefits. Therefore, men have a younger age of peak onset,
potentially because they lack estrogen to act as a mediator for the illness (Wu
et al., 2013). As well, levels of estrogen decline with age in women, which may
be playing a factor in later age of schizophrenia onset, especially after the
age of 45, when women typically begin to experience menopause, and their
estrogen levels rapidly decline (Hill, 2015; Wu et al., 2013).

            Likewise,
brain-derived neurotrophic factor (BDNF) is involved with proper neurological
function. Specifically, BDNF regulates synaptic plasticity and long-term
potentiation – both of which are considered to affect learning and memory (Wu
et al., 2013, p. 70). Alterations in neurotrophins, such as BDNF, are believed
to contribute to the development of schizophrenia. Specifically, a polymorphism
in the BDNF gene at codon 66 from Valine to Methionine has shown that altered
levels of BDNF are released (Chen et al., 2004). Many studies have found a link
between this polymorphism and schizophrenia (Wu et al., 2013). For instance,
the authors state that variants in BDNF genes have been shown to affect verbal
tasks, brain blood flow, and brain volume.  

            However
interesting as individual parts, the interaction between estrogen and BDNF
factors greatly into schizophrenia. Estrogen acts through various estrogen
receptors (ER), and what is important is action can only take place once
estrogen binds and causes a conformational change in the ER, allowing it to
bind to an estrogen response element (ERE) – thus, causing a response (Wu
et al., 2013). Interestingly, the same authors cite that BDNF contain ERE-like
sequences, suggesting that estrogen can modulate their expression.

As previously stated, estrogen and BDNF contain neuro-protective properties.
These protective effects also seem to only benefit women, and this is
especially seen through their interaction. If an individual is lacking
estrogen, they may also be lacking the ability to fully express BDNF because of
its ER regulated properties.