Schizophrenia antipsychotic action

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). 

Fluanisone is a neuroleptic with sedative properties and relatively poorly expressed antipsychotic action. It is used as an independent or adjuvant drug for psychomotor excitement in severe and chronic schizophrenia and for manic-depressive disorder. Synonyms of this drug are sedalande, methorin, and others. 

After dopamine was identified as a neurotransmitter in 1959, it was shown that its effects on electrical activity in central synapses and on production of the second messenger cAMP by adenylyl cyclase could be blocked by antipsychotic drugs such as chlorpromazine, haloperidol, and thiothixene. This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine-receptor antagonists and was responsible for the dopamine hypothesis of schizophrenia described earlier in this chapter. The antipsychotic action is now thought to be produced (at least in part) by their ability to block dopamine in the mesolimbic and mesocortical systems. 

Extension of this specificity principle to the clinical domain has resulted in the availability of increasingly well-aimed chemical bullets. If we wanted to block just one of the many serotonin receptors to see what would happen, we could probably do it But if we wanted to elevate mood in depression—or obsessive-compulsive disorder—would we expect the best result if we blocked just that one receptor And if we wanted to discourage auditory hallucinations in schizophrenia, would we want our drug to target only D2 dopamine receptors, even if we knew that the antipsychotic action of drugs correlated well with a drug s affinity for those receptors ... 

Benzodiazepines are used as hypnotics because they have the ability to increase total sleep time. They demonstrate minimal cardiovascular effects, but do have the ability to increase heart rate and decrease cardiac output. Most CNS depressants, including the benzodiazepines, exhibit the ability to relax skeletal muscles. Clozapine, a dibenzodiazepine, is used in the treatment of schizophrenia. It has both sedative and antipsychotic actions, and is the only FDA-approved medication indicated for treatment-resistant schizophrenia, and for reducing the risk of suicidal behavior in patients with schizophrenia. This drug can have potentially life-threatening side effects, but appears to have no abuse potential and will not be considered further. 

The earliest effective treatments for schizophrenia and other psychotic illnesses arose from serendipitous clinical observations rather than from scientific knowledge of the neurobiological basis of psychosis or the mechanism of action of effective antipsychotic agents. Thus, the fist antipsychotic drugs were discovered by accident in the 1950s when a putative antihistamine (chlorpromazine) was serendipitously observed to have antipsychotic effects when tested in schizophrenic patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions in schizophrenia are not mediated by this property. Once chlorpromazine was observed to be an effective antipsychotic agent, it was tested experimentally to uncover its mechanism of antipsychotic action. 

Cannabinoid antagonists. Cannabinoid receptors are discussed in further detail in Chapter 13 on drug abuse. An antagonist to cannabinoid 1 (CB1) receptors, SR141716A, reduces the activity of mesolimbic dopamine neurons in animal models, suggesting possible antipsychotic actions in schizophrenia and leading to testing in schizophrenic patients. 

The dopamine hypothesis of schizophrenia posits that such symptoms arise because of a functional excess of dopaminergic activity in the CNS. The notion is based on the facts that drugs that activate DA receptors may cause psychotic symptoms and those that block DA receptors often have antipsychotic actions. However, drugs used for schizophrenia do not remedy all symptoms they are not curative, and some newer agents appear to be effective in many patients, even though they do NOT act as antagonists at brain DA receptors but may modify serotonin functions. 

Miyamoto S, Dnncan GE, Marx CE, et al. Treatments of schizophrenia a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005 10 79-104. 

Chlorprothixene has an antipsychotic and sedative action. It has expressed antiemetic activity. It is used in various psychoses, schizophrenia, reactive and neurotic depression with prevalent anxious symptomatology, and in conditions of excitement associated with fear and stress. It may be used in small doses as a sedative agent in neurosis. Synonyms of chlorprothixene are clothixene and tarasan. 

Fluphenazine (Prolixin, Permitil) [Antipsychotic/ Phenothiazine] Uses Schizophrenia Action Phenothiazine antipsychotic blocks postsynaptic mesolimbic dopamin gic brain receptors Dose 0.5-10 mg/d in % doses PO q6-8h, av age maint 5 mg/d or 1.25 mg IM, then... 

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