Reserpine schizophrenia

In 1952 reserpine, an alkaloid extract from the Indian snakewort plant, Rauwolfia serpentina, which had been used in that country to treat madness , was first tried in schizophrenia. The beneficial impact on patients and the hospital wards was dramatic, as was that a year later of chlorpromazine, a phenothiazine derivative and haloperidol, a butyrophenone. These latter two drugs and closely related derivatives remained the mainstay of therapy for almost 40 years. 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

Reserpine A drug extracted from Rauwolfia serpentina which was once clinically used in the treatment of essential hypertension and schizophrenia. 

The two pioneer drugs for schizophrenia are chlorpromazine and reserpine. Reserpine is known to reduce the brain levels of norepinephrine, dopamine, and serotonin. Since reserpine is also effective in coping with some of the symptoms of schizophrenia, perhaps an abnormally high concentration of one or more of these monoamines is a contributing factor to this disorder. 

It became known in the same year (1954) that the substance reserpine, derived from the Indian plant Rauxcolfia serpentina, had antipsychotic effects similar to those of chlorpromazine This finding was of interest for two reasons the molecular structure of reserpine has some similarity to that of serotonin and LSD and it was found that reserpine liberates serotonin from presynaptic stores in the CNS and thus produces a short-lived excess supply of functionally available serotonin at the synapse. In the context of a serotonin hypothesis of schizophrenia, it could be postulated that the antipsychotic effect of reserpine was due to its ability to liberate serotonin presynaptically and make it functionally available. However, despite its scientific appeal, the serotonin hypothesis of schizophrenia did not last long because it was in conflict with both psychopathological and pharmacological findings ... 

Rauvolfia verticilata (Lour.) Baill. Luo Fu Mu (root) Reserpine, rescinnamine, beta-sitosterol, aricine, vellosimine, peraksine, serpentine, robinin.33-39-510 Treat hypertension, psychosis, schizophrenia. 

It potentiates (already in low doses) the excitement syndrome induced by DOPA and simultaneously annihilates the depression caused by reserpine. In man, 74 seems to be useful in the treatment of psychoses and schizophrenia. 

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. 

Carlsson discovered that DA is present in large amounts in the brain, and disappears when a person is given the drug reserpine. Administration of the precursor of DA, L-dihydroxyphenylalanine (L-dopa), brings about the reappearance of DA in the brain. Carlsson said, I would put the discovery of dopamine and its role for normal brain functions as a winner, no doubt about it. A good second place would go to the research into the role of dopamine in mental disorders, such as schizophrenia, followed by the third finding the mode of action of antipsychotic drugs. ... 

For centuries, people have used herbal medicines to help patients with schizophrenia. In India and the East Indies, Rauwolfia serpentina offered some hope, and was used for a long time to treat Chandra, i.e., moon disease or lunacy. The roots of Rauwolfia yielded the drug reserpine, the first major tranquilizer, adopted by Western medicine in 1943 and first used to treat hypertensive patients in the 1950s. Before that, it had been used in India in millions of patients. 

A prolonged period of increased motor activity after starting reserpine ( reserpine-reversal ) possibly occurred in 3 patients with schizophrenia treated firstly with phenelzine for 12 weeks, then a placebo for 16 to 33 weeks, and lastly reserpine for 12 weeks, when compared with patients receiving reserpine who had not received an MAOI. Their blood pressures rose slightly and persistently, and their psychomotor activity was considerably increased, lasting in two cases throughout the 12-week period of treatment. ... 

Tetrabenazine was synthesized in the 1950s as part of research into compounds with reserpine-Uke activity and was initially used in the treatment of schizophrenia. Its common reversible adverse effects include drowsiness/sedation, weakness, parkinsonism, depression, and acute akathisia. 

Finally, the possible role of endogenous histamine in the CNS has been investigated. This histamine comes from the histidine which has been transformed in situ by cerebral histidine decarboxylase, since histamine cannot cross the blood-brain barrier. It is difficult to determine exactly how much histamine the CNS contains since assays are rendered imprecise by chemical interference, but it appears that histamine behaves at this level like the catecholamines and S-hydroxytryptamine under the influence of reserpine. The hypothalamus is rich in histidine decarboxylase and in histamine, but the way in which the histamine is distributed is altogether different from that of the other amines. This histamine is governed by the action of methyltransferase, which in turn is inhibited by chlorpromazine. The question of whether histamine is somehow related to schizophrenia is still being debated. 

---