Age of onset[edit]

In support of the above mentioned conclusions many studies have been performed. Doctors Lindamer, Lohr,
Harris, and Jeste conducted a study to determine age of onset of schizophrenia in which they examined gender
differences in 194 patients ranging in age from 35 to 97. They found that the mean age for onset in men was
30, while in women it was 39.
[1]
(It is important to note that this is just one study, and overall averages come
from a combination of different studies). About 37% of the women developed schizophrenia at the age of 45,
while only 16% of men reported the same.
[1]
Thus, more women than men experience late onset
schizophrenia.
[1]
This indicates that there is indeed another peak for women at the age of 45 and women do
develop schizophrenia later in life. These factors have led researchers to believe that estrogen may have an
effect on psychosis in women.
[1]

Another study was conducted on older men and women to determine how schizophrenia affects them. The
study consisted of 36 women and 86 men, all of similar age. More women than men were found to
have paranoid schizophrenia and suffered more from severe positive symptoms rather than negative
symptoms.
[1]
All of this information is consistent with other studies showing that women have a later age of
onset of schizophrenia and suffer more from severe positive symptoms rather than negative symptoms.
[1]

Differences in coping with schizophrenia in men and women[edit]
Studies suggest that women are better at coping with schizophrenia than men. Not only do women show
fewernegative symptoms, but they respond better to antipsychotics. Having healthier social and family lives
also appear to make women less susceptible, and result in and fewer hospitalizations.
[3]
Women also tend to
have an overall higher percentage of recovery for all age-groups, although only by a small margin.
[3]

Estrogen and dopamine[edit]
Genetic factors have much to do with developing schizophrenia.
[4]
In fact the heritability of schizophrenia is
around 80%, and a first degree relative has a 5 to 10 fold increase in the risk of developing the disorder
compared to the risk for the general population.
[4]
It seems that individuals with schizophrenia inherit
problems associated with dopamine in the brain. According to Answers.com, dopamine is a neurotransmitter
essential to the normal functioning of the central nervous system.
[5]
In the 1950s Arvid Carlsson designated
the molecule dopamine,,as a neurotransmitter.
[6]
This led to the dopamine hypothesis of schizophrenia.
Animal studies provide evidence that estrogen regulates dopamine systems.
[1]
In the studies performed on
animals estrogen seems to act as a barrier to dopamine receptors.
[1]
Thus estrogen may prevent the increase
in dopamine found in patients with schizophrenia. This directly supports the idea that estrogen acts as a
deterrent. This would explain why women have peak in the onset of schizophrenia in their late forties since at
this time estrogen levels drop in women, causing the dopamine to increase, resulting in psychotic symptoms.
Biochemical studies prove contradictory to this approach. In these studies the estrogen either increased or
decreased dopamine receptors, depending on the time allotted for the experiment.
[1]
This contradicts the
theory that estrogen inhibits dopamine receptors, therefore acting as a protectorate against schizophrenia.
However, these studies provide evidence that estrogen does indeed have some effect on the release
of dopamine. Whether or not it acts a protectorate or not, if further studied it could lead to a better
understanding of schizophrenia and why it occurs later in women when their estrogen levels have gone down.
At the same time errors could have occurred as the studies were done on animals rather than humans.
*So what causes schizophrenia?
The most widely accepted hypothesis of the mechanism of schizophrenia is based on the action
of dopamine, a major neurotransmitter in the brain. Early in schizophrenic research it was noticed that all the
effective anti-psychotic drugs reduced dopamine activity. Recent studies have shown that in schizophrenics,
very high levels of dopamine are found in a part of the brain called the striatum, but strangely,
the striatum has a normal amount of dopamine receptors. However, the prefrontal cortex in brains of
schizophrenics has an unusually low amount of receptors (7). The idea that has become popular is that in a
normal brain the activity of dopamine going on in the prefrontal cortex slows down the development of
dopamine pathways in the striatum. In a schizophrenic brain, however, for some reason there is little
dopamine activity in the prefrontal cortex, so there is nothing to slow down the dopamine in the striatum and
it grows disastrously. It is thought that the lack of dopamine activity in the prefrontal cortex could cause
the negative symptoms seen in schizophrenics like lack of emotion and social interaction and the abundance in
the striatum could cause the positive symptoms like delusions and incoherent thoughts (3).

*What exactly is estrogen and how does it work in the body?
Estrogen is actually a generic term that encompasses several different types of similar female
hormones. The most potent form of estrogen is generally considered to be estradiol, which is the type used in
many of the studies we describe.
Estrogens achieve their effects in the body by changing the expression of certain genes in target
cells. Estradiol is soluble in cell membranes, so it can pass easily into the cell. Once inside it binds with
an estrogen receptor. Estradiol will then fit into a specific site on the receptor specially coded for estrogen, so
while it can probably enter many cell types, only the ones with estrogen receptors can respond to it (14). For
a long time it was unclear why estrogen seemed to cause effects in aspects of the body like the cardiovascular
and skeletal systems, which had little to do with the sexual and hormonal effects estrogen was associated
with. Presumably the cells would have no need of receptors for estrogen to bind to and how estrogen affected
these systems was a mystery. Now scientists believe there are two types of estrogen receptors, ER-alpha and
ER-beta. ER-alpha receptors are associated with the traditional female sexual effects of estrogen and is found
in the uterus, tests and adrenal gland. While ER-beta is present here to a degree, it is found in more diverse
parts of the body, including the brain. ER-beta is localized in the learning and memory regions of the brain,
implying that these receptors play a major part in estrogen's action in the schizophrenic brain (11).
When two receptors are occupied by estrogen molecules, they come together to form a dimer. The dimer
then attaches to a regulating site on a gene called the estrogen response element, or ERE which is on the
gene's promoter, or its on switch. The dimerized molecules interact with proteins linked
with transcription factors on the gene's promoter, and in this way regulate gene expression. Through estrogen
binding, gene expression can be turned on, modified, or suppressed completely (14).
Some suggest that estrogen could also act on the brain by sharing pathways with neurotrophins, because
their receptors are found in the same neurons. Estrogen may be able to enter the cell and activate ERKs that
could relay neurotrophin signals to the nucleus, without the estrogen actually having to bind to the receptor
(15).

*Why do scientists think estrogen is involved in schizophrenia?
A puzzling trend has been evident to schizophrenia researchers for years: a discrepancy between the
average age of diagnosis in men and women. It has been shown in almost every demographic study that the
peak age of schizophrenia diagnosis in men is about five years earlier than the peak in women. Women's
symptoms also tend to be less severe than men's.
Another interesting trend is that, in addition to the first peak in diagnosis that women show several years
later than men, women show another peak in diagnosis between the years of 45 and 49, which is completely
unmatched in men (4).
Because this second peak corresponds to the age of menopause, these trends were the first suggestion that
estrogen might have a delaying effect on schizophrenia. It seems likely that the presence of estrogen
prevents the development of schizophrenia in women at high risk for the disease, but when they lose their
estrogen during menopause, the disease takes over.
Since this first indication, many studies have shown a connection between estrogen and
schizophrenia. Research has shownsymptoms are often reduced when estrogen is high; fewer relapses tend to
occur during pregnancy, a time of high estrogen levels. On the other hand, symptoms tend to worsen around
menstruation when estrogen levels are low (4). Also, women are often more responsive
to neuroleptic treatment than men.
All of these trends seem to indicate that estrogen definitely has a delaying effect on schizophrenia, but the
question still remains how it affects the course of the disease. Here several possible mechanisms are
suggested by which estrogen might delay schizophrenia, but it is still unknown which, if any of them, is
correct; further research needs to be done.
*First possible estrogen mechanism: Blocking Dopamine Receptors
The most common class of drugs used to help schizophrenia, neuroleptics, work by blocking and disabling
the dopamine receptors in the brain (7). The prevailing opinion on the mechanism of estrogen in
schizophrenia is that it works in a similar way.
A study done on rats that had been dosed with a psychotic drug showed that the dissociation constant K
d
of
the binding of a dopamine receptorligand was 2.8 times higher in a group treated with estrogen, which showed
that the receptors treated with estradiol had less of an affinity to the ligand. These researchers concluded that
estrogen treatment reduced the sensitivity of the dopamine receptors, blockading them like neuroleptics. This
is supported by the fact that, like estrogen, neuroleptics also reduce the worst symptoms and can delay
relapses, but don't seem to reduce the lifetime risk of developing the disease (4).
Another researcher reported that estrogen had an effect on dopamine activity in the nucleus accumbens by
in a way slowing down the process; inhibiting the release of dopamine, as Hafner et al suggested, and also,
she claimed, by prolonging the uptake process of extra dopamine to the receptors. The idea is that by slowing
the process, estrogen, like neuroleptics, would return dopamine sensitivity to the receptors and would
normalize the amount of dopamine in the system (5).
Only a few studies have specifically targeted estrogen's interaction with dopamine, so it is still largely
uncertain as to whether estrogen directly affects dopamine activity as these scientists suggest. Other research
suggests that estrogen may take another route to delay schizophrenia.
*Second possible estrogen mechanism: Inhibiting Cytokines
Recently research has been done on the role of protein activity on schizophrenia. Protein molecules have
been shown to play a part in normal development of neurons in the brain by stimulating some receptors on the
surface of dividing cells. One type of stimulator is a class of molecules called cytokines. Several studies have
been done on the effect of cytokines in schizophrenia, but the researchers have come to rather different
conclusions. Some scientists have shown that the schizophrenic brain has a markedly lower amount of
neurons. They hypothesized that this was due to a lower amount of cytokines which would limit neuron
development (12). However, this idea is contradicted rather conclusively by another study which seemed to
show that cytokines have a definite worsening effect on schizophrenia.
Researchers tested the brains of schizophrenics for the cytokine Interleukin-2 while they were
on neuroleptic medication. They found that schizophrenics who had a relapse tended to have significantly
higher levels of Interleukin-2 than those who didn't relapse. This suggested to the researcher that too many
cytokines might affect the normal regulation of dopamine (6).
Although the exact mechanism by which the cytokines might worsen the symptoms of schizophrenia is
unknown, the fact that they are involved suggests another possible avenue by which estrogen might inhibit
dopamine and thus schizophrenia. While no studies to our knowledge have been done on estrogen and
cytokines in the brain, they have been linked in another body system: the skeleton.
Studies have shown that estrogen helps keep bones strong and that lack of estrogen is one reason for
osteoporosis. We know that there are two major types of cells in bone, osteoblasts which form bone and
osteoclasts which break down bone. In a normal body they are in an efficient balance of renewal. Cytokines
in the bone are the agents that start osteoclasts on their task of destruction by binding to them (10).
Researchers have found that in the presence of estrogen, the amount of signal proteins on the osteoclasts
which draw cytokines is lower and the number of fake, decoy proteins increase. This prevents cytokines from
binding and thus causes fewer osteoclasts and less bone destruction. After menopause, the estrogen can no
longer exert a protective force and the cytokines flourish, causing bone destruction (10).
It seems very possible that the effect of estrogen on cytokine production in the bone might also be
replicated in a related way in the brains of schizophrenics, given the cytokine-schizophrenia connection
established by McAllister and the beneficial effects of estrogen on schizophrenics. One interesting note in the
osteoporosis study was that estrogen had no effect on the receptors in the beneficial bone forming osteoblast
cells, but seemed to selectively affect the osteoclasts. Perhaps estrogen might work similarly in the brain,
showing little effect on cytokines in the normal brain but exerting a regulating effect when necessary in
schizophrenic brains. Estrogen might create decoy proteins in the brain as well, to keep cytokines from
binding to dopamine receptors and stimulating their unchecked growth. However, this is just
speculation. Research in the future could try to determine if estrogen has an effect on the levels of
Interleukin-2 in the schizophrenic brain; if not, other possibilities must be examined.
*Third possible estrogen mechanism: Increasing neuronal connections through NMDA
In the past studies have suggested that in schizophrenic brains the number of connections between brain
cells were reduced (8). Creating another hypothesis of the mechanism of estrogen, some researchers have
found that addition of estrogen to the brain cells increased the density of dendritic spines. A similar study
found a connection between estrogen and NMDA receptors. They found that NMDA-antagonists blocked the
densifying effect of estrogen, implying that estrogen works through the NMDA receptors (13). This makes
sense because PCP, a drug that inhibits NMDA, has long been known to cause psychotic symptoms (8). So
possibly estrogen works through NMDA receptors to increase the number of connections in the schizophrenic
brain, and in this way alleviates the symptoms of schizophrenia, rather than working through dopamine.

*Fourth possible estrogen mechanism: Increasing serotonin activity
Another pathway estrogen might take in prohibiting schizophrenia is
through serotonin receptors. Researchers have found a decrease in the density of serotonin binding in
schizophrenics, implicating a lack of serotonin activity as a possible cause of the disease (2). One study has
shown that estrogen treatment in rats that were previously castrated seems to benefit the serotonin
transmitter system in their brain. Possibly estrogen works its beneficial effects on the schizophrenic brain by
increasing serotonin activity.
Etiology
The causes of schizophrenia are not known. Most likely, there are at least 2 sets of risk factors, genetic and
perinatal. In addition, undefined socioenvironmental factors may increase the risk of schizophrenia in
international migrants or urban populations of ethnic minorities.
[16, 17, 18]
Increased paternal age is associated
with a greater risk of schizophrenia.
Genetic factors
The risk of schizophrenia is elevated in biologic relatives of persons with schizophrenia but not in adopted
relatives.
[19]
The risk of schizophrenia in first-degree relatives of persons with schizophrenia is 10%. If both
parents have schizophrenia, the risk of schizophrenia in their child is 40%. Concordance for schizophrenia is
about 10% for dizygotic twins and 40-50% for monozygotic twins.
Genome-wide association studies have identified many candidate genes, but the individual gene variants that
have been implicated so far account for only a small fraction of schizophrenia cases, and these findings have
not always been replicated in different studies. The genes that have been found mostly change a genes
expression or a proteins function in a small way.
In a 2014 study, researchers identified new genetic loci not previously known to be associated with
schizophrenia. Of the 108 genetic loci linked to schizophrenia that were identified in the study, 83 had not
previously been found. The investigators also determined that among 128 independent associations related to
the 108 loci, enriched associations existed not only among genes expressed in the brain, but also among those
expressed in tissues related to immunity, giving support to the theory linking the immune system to
schizophrenia.
[20, 21]

he causes of schizophrenia, like all mental disorders, are not completely understood or known at this time.
There is no known single cause of schizophrenia. Many diseases, such as heart disease, result from an
interplay of genetic, behavioral and other factors, and this may be the case for schizophrenia as well.
Scientists do not yet understand all of the factors necessary to produce, but all the tools of modern biomedical
research are being used to search for genes, critical moments in brain development, and other factors that
may lead to the illness.
Can Schizophrenia Be Inherited?
It has been long understood that schizophrenia runs in families. People who have a close relative with
schizophrenia are more likely to develop the disorder than are people who have no relatives with the illness. A
child whose parent has schizophrenia has about a 10 percent chance of developing schizophrenia themselves.
A monozygotic (identical) twin of a person with schizophrenia has the highest risk a 40 to 65 percent chance
of developing the illness. People who have second-degree relatives (aunts, uncles, grandparents, or cousins)
with the disease also develop schizophrenia more often than the general population. By comparison, the risk of
schizophrenia in the general population is about 1 percent.
Scientists are continuing to study and better understand the genetic factors related to schizophrenia. We
inherit our genes from both parents. Scientists believe several genes are associated with an increased risk of
schizophrenia, but that no gene causes the disease by itself. In fact, recent research has found that people
with schizophrenia tend to have higher rates of rare genetic mutations. These genetic differences involve
hundreds of different genes and probably disrupt brain development.
In addition, factors such as prenatal difficulties like intrauterine starvation or viral infections, perinatal
complications, and various nonspecific stressors, seem to influence the development of schizophrenia.
However, it is not yet understood how the genetic predisposition is transmitted, and it cannot yet be accurately
predicted whether a given person will or will not develop the disorder.
Other recent studies suggest that schizophrenia may result in part when a certain gene that is key to making
important brain chemicals malfunctions. This problem may affect the part of the brain involved in developing
higher functioning skills.Research into this gene is ongoing, so it is not yet possible to use the genetic
information to predict who will develop the disease.
In addition, it probably takes more than genes to cause the disorder. Scientists think interactions between
genes and the environment are necessary for schizophrenia to develop. Many environmental factors may be
involved, such as exposure to viruses or malnutrition before birth, problems during birth, and other not yet
known psychosocial factors.