The pathophysiology of schizophrenia has long remained a mystery and still today, even with various

hypotheses, remains somewhat uncertain: there are too many variants; not enough consistency in
findings; and, despite research, a lack of documented proof.
The most well-known and respected hypothesis with regards to the pathophysiology
ofschizophrenia began in the 1990s and consisted primarily of the notion there is a problem with the
dopamine levels in the brain of schizophrenics.
Dopamine is both a hormone and a neurotransmitter, which means that it activates five different receptors
in the brain, aptly named D1, D2, D3, D4, and D5. That said, it may not be the only neurotransmitter
involved in the pathophysiology of schizophrenia. Glutamate and Serotonin have also been implicated. .
Contributing to this hypothesis is the fact that drugs administered to aid dopaminergic activity bring on
schizophrenic characteristics such as psychosis, in a patient, whereas drugsadministered to block them
help reduce, or eliminate symptoms of schizophrenia altogether.
Additional studies affecting the pathophysiology of schizophrenia include suggestions that maternal factors such as
infection, malnutrician, location of birth, season of birth, and delivery, may play a significant part in the formation
and subsequent appearance of schizophrenia. Studies have shown that the worldwide rate of births affected
with schizophrenia is up to 8% higher when occurring in spring or winter, though no explanation for this can be
offered.
Another aspect of the pathophysiology of schizophrenia that has been explored in relative detail is that
of genetics, and their relation to the likelihood of immediate relatives being born with the disease.
Shockingly, it has been found that 10% of all immediate family members of an infected person will be
struck down with the disease. This is specifically in relation to parents, siblings, and children. With regards
to twins or other multiple births, the chances they will share the disease is 50%. Genetic reports suggest
that it is the X chromosome which determines whether or not a person is infected with schizophrenia,
specifically, chromosomes 1, 3, 5, and 11, however further studies are needed in order to prove this
theory.
Though there are many theories and hypotheses regarding the pathophysiology of schizophrenia, there
is, unfortunately, still no cure for the disease. The best a sufferer can hope for nowadays is to benefit from
available medication which keeps the disease under control or in remission for the duration of time for
which it is taken.

Schizophrenia: Pathophysiology
Schizophrenia is characterized both by gross anatomic pathology and by microscopic neuropathology
of the prefrontal cerebral cortex, the hippocampus, and related limbic structures. In vivo
neuroradiological studies and postmortem brain analyses demonstrate enlargement of the ventricular
system. Neuroimaging studies are consistent with loss of cortical volume in the prefrontal cortex and
in the region of the hippocampus.In addition, magnetic resonance spectroscopy reveals a reduction in
concentration of multiple neuronal markers limited to the dorsolateral prefrontal cortex and the
hippocampal region. There are, however, neuroimaging studies that have found abnormalities in the
thalamus, a structure that interacts with essentially all regions of the cerebral cortex and with the
striatum. As methods of data normalization for the normal variance in head size and brain architecture
are developed, brain abnormalities associated with schizophrenia should come into sharper focus.
Many quantitative studies of brain morphology have suffered from the wide variations in normal
control populations. One study addressed this problem by using a cohort of 15 monozygotic twin pairs
who were discordant for schizophrenia. In 14 of the pairs, the schizophrenic twin had a smaller
anterior hippocampus on the left; in 13 of the pairs, the schizophrenic twin had a smaller anterior
hippocampus on the right. Compared with their normal co-twins, 14 of the twins with schizophrenia
had enlarged left lateral ventricles and 13 had enlarged right lateral ventricles. The third ventricle was
also larger in 13 of the 15 schizophrenic twins. Such differences were not found in either hippocampal
size or ventricular volume in seven sets of monozygotic twins without schizophrenia who served as
control subjects. This study demonstrated an important role for nongenetic factors in the pathogenesis
of schizophrenia, in that affected and unaffected co-twins showed significant differences in brain
morphology despite being genetically identical.
Whether these gross anatomic abnormalities bear a cause-and-effect relation to the primary disease
process remains unclear. It is significant that ventricular enlargement can be detected even with new
onset of active schizophrenic symptoms, because it suggests that the anatomic abnormalities
antedate the onset of symptoms of schizophrenia. Moreover, neither gliosis nor inflammatory cells
have been found in neuropathological studies, which rules out an active neurodegenerative process.
Taken together, these data are consistent with a brain lesion that occurs early in life and acts in
conjunction with a genetic predisposition to schizophrenia to produce symptoms that appear at a later
time. The possible causes of the observed tissue loss are currently the subject of intensive research.
Some studies suggest that the tissue loss results from a disruption of neuronal migration during
morphogenesis of the cerebral cortex.
Neuropsychological studies and neuroradiological findings also indicate clear abnormalities of frontal
lobe function in schizophrenic patients. Positron emission tomography (PET) and single-photon
emission computed tomography (SPECT) in schizophrenic patients have revealed decreased frontal
lobe metabolism (so-called hypofrontality) that is independent of medication status. When
schizophrenic patients are given tasks that require frontal lobe activation, they perform poorly. This
impaired performance correlates with the failure of frontal lobe neurons to activate normally in
response to the task.
The prefrontal cortex and the limbic structures implicated by these anatomic and function studies are
richly innervated by dopamine-mediated pathways. This finding helps explain the efficacy of
antipsychotic drugs that act as dopamine receptor antagonists, although the precise mechanism by
which they alleviate the symptoms of schizophrenia remains unknown.
There are currently five known types of dopamine receptors, designated D1 to D5. Abnormalities in
receptor number or function have been postulated to be associated with symptoms of schizophrenia,
but studies to confirm this belief have been made difficult by the dearth of well-characterized patients
who have never received antipsychotic drugs, which may cause alterations in dopamine receptors.
Most recently, it has been reported that D1dopamine receptors are decreased in the prefrontal cortex
of drug-naive and drug-free persons with schizophrenia. If replicated, this finding is of interest
because D1 dopamine receptors have been shown to play a role in working memory, a form of short-
term memory that is impaired in persons with schizophrenia.