THE DISEASE OF
SCHIZOPHRENIA
Schizophrenia is a group of
heterogeneous, chronic psy-chotic disorders. Key symptoms include
hallucinations, delusions, and abnormal experiences, such as the per-ception of
loss of control of one’s thoughts, perhaps to some outside entity. Patients
lose empathy with others, become withdrawn, and demonstrate inappropriate or
blunted mood. Discrimination of several subtypes of the disease represents only
different patterns of symp-toms with little value in relating behavior to
neu-ropathology. The disorder has a strong genetic compo-nent, as demonstrated
by a concordance of 40 to 50% between monozygotic twins, but no objective
physiolog-ical or biochemical diagnostic tests exist.
Schizophrenic symptoms have
been divided into two major categories. Positive
symptoms are those that can be regarded as an abnormality or exaggeration
ofnormal function (e.g., incoherent speech, agitation). The antipsychotic drugs
are generally more effective in con-trolling these signs. Negative symptoms are those that indicate a loss or decrease in
function, such as poverty of speech content or blunted affect. Both types of
fea-tures are observable in most patients. Negative signs are considered to be
more chronic and persistent and less responsive to some antipsychotic agents.
Although any of these symptoms may undergo partial remission, per-sistent
dysfunction and exacerbations are typical.
Schizophrenic patients appear
to have small brains with large ventricular volumes, indicating a relative
deficit of neurons. Structural and functional brain imag-ing studies have
strongly suggested that regions of the medial temporal lobe (e.g., hippocampus)
have dimin-ished numbers of neurons and also have demonstrated the inability of
individuals with schizophrenia to acti-vate the frontal cortex and successfully
execute tasks that require frontal cortical function. However, the
re-lationship between behavioral signs, neuropathology, and a postulated
functional excess of dopamine (dis-cussed later) is unknown, and no theory of
causation is conclusive.
The dopamine hypothesis of
schizophrenia is the most fully developed theory of causation for this
disorder, and until recently, it has been the foundation for the ra-tionale
underlying drug therapy for this disease. The hy-pothesis is based on multiple lines
of evidence suggest-ing that excessive dopaminergic activity underlies
schizophrenia: (1) drugs that increase dopaminergic ac-tivity, such as levodopa
and amphetamines, either ag-gravate existing schizophrenia or induce a
psychosis in-distinguishable from the acute paranoid form of the disorder; (2)
traditional antipsychotic drugs strongly block D2-dopaminergic
receptors in the central nervous system (CNS), and clinical efficacy is highly
correlated with the potency of individual agents to bind to this re-ceptor; (3)
some postmortem studies have reported in-creases in dopamine receptor density
in brains of schizophrenics who were not treated with antipsychotic drugs; and
(4) clinical response to antipsychotic drug treatment is correlated with a
decrease in homovanillic acid, a primary dopamine metabolite, in cerebrospinal
fluid (CSF), plasma, and urine.
However, the dopamine
hypothesis does not ac-count for some important observations. If an
abnormal-ity of dopamine physiology were solely responsible for the
pathogenesis of schizophrenia, antipsychotic drugs would do a much better job
in treating patients. As it is, they are only partially effective for most and
ineffective for some patients. Moreover, there is evidence that diminished
glutamatergic activity also plays a role inthe disease. The primary defect
could emanate from nondopaminergic systems that exert a regulatory effect on
dopamine neurons, leading to disinhibition of some dopaminergic pathways.
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