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Chapter: Modern Pharmacology with Clinical Applications: Antipsychotic Drugs

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The Disease of Schizophrenia

Schizophrenia is a group of heterogeneous, chronic psy-chotic disorders.

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 Patients lose empathy with others, become withdrawn, and demonstrate inappropriate or blunted mood.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

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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