Can abnormalities in the "steady state" of biogenic amines (NE, DA, 5-HT) and other neurotransmitters of the CNS be causative factors in mental diseases such as schizophrenia, endogenous depression, and manic behavior? Only 50 years ago arguments in favor of such a notion would have elicited, at best, benign smiles of amusement from an audience of psychiatrists.
It is interesting that some experiments in the 1880s had suggested a possibility of chemical factors affecting the pathology of psychoses. If the state of organic and analytical chemistry is considered, it is understandable that some of these early "results" were not reproducible. However, things changed dramatically by the 1950s, mainly due to the discovery of drugs that were able to affect significantly and positively—even if palliatively— mental illness.
Research over the past several decades has resulted in interesting theories involving these amines and their receptors. It should be pointed out, however, that these concepts are still theories, not established explanations of the disease state.
Following the empirically based introduction of psychotropic drugs in the early 1950s, it was observed that some tended to normalize mood swings. It was further noted that brain amine levels of patients suffering from affective pathophysiology (e.g., endogenous depression) were also normalized.
Furthermore, the rauwolfia alkaloids (reserpine and others), which also began to be used at that time in psychiatry (and as antihypertensives; see Chapter 10), were found to be potent depletors of brain NE and 5-HT in animals. These and additional findings over the next decade led to the (mono)amine hypothesis of mental disorders. The DA hypothesis of schizophrenia is currently the one with the most supportive evidence.
The neuroleptic phenothiazines (available then) to treat schizophrenic symptoms were shown to decrease central DA transmission. The DA synthesis inhibitor a-methyltyrosine can potentiate these drugs. On the other hand, drugs known to enhance central DA activity can worsen symptoms and even produce psychotic-type signs in normal individuals. MAO inhibitors, by retarding biogenic amine breakdown, are good examples. The antipsychotic phenothiazines (see Table 12-11), as well as apparently chemically diverse drugs with clinically effective antipsychotic activity, all have the ability to affect DA negatively. This includes the butyrophenones and diphenylbutylamines (see Table 12-12), dibenzoxazepines (see Table 12-13), and dihydroindolone compounds (see later). It is now reasonably well established that all these drugs are capable of blocking DA receptors in the brain.
There are three major central DA pathways: the nigrostriatal, which is affiliated with motor effects produced by antipsychotic drugs; the tuberoinfundibular tract, which is asso-
Table 12-11. The Neuroleptic Phenothiazines and Thioxanthenes
A. Dialkylaminopropyl group
CI Antiemetic, sedation
2. Promazine (Sparine)
3. Triflupromazine (Vesprin)
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