Antipsychotic effect

The second theory is that some atypicals work by balancing dopamine blockade with serotonin receptor blockade. We know that one of the roles of serotonin is to attenuate (or lessen) dopamine activity. Blocking serotonin action therefore may release just enough dopamine activity in the nigrostriatal pathway to avoid EPS without interfering with the antipsychotic effects in the mesolimbic area. 

The antipsychotic effect is probably due to an antagonistic action at dopamine receptors. Aside from their main antipsychotic action, neuroleptics display additional actions owing to their antagonism at... 

Derivatives bearing a piperazine moiety (e.g., trifluperazine, fluphena-zine) have greater antipsychotic potency than do drugs containing an aliphatic side chain (e.g., chlorpromazine, triflu-promazine). However, their antipsychotic effects are qualitatively indistinguishable. 

Although normally administered in comparatively large doses the concentration of unaltered chlorpromazine in plasma is usually too low to be measured except by sensitive GLC methods (C6, C15). Using such a technique, Curry et al. (C18) have shown that the optimum antipsychotic effect appears to occur at plasma levels which are lower than those causing side effects in chronically treated patients but higher than those causing these effects in acutely treated patients. ... 

Buspirone was developed in the late 1960s with the intent of developing a better neuroleptic. Clinical trials demonstrated little antipsychotic effects however, animal models suggested some anxiolytic effects. The drug was marketed as an anxiolytic in 1986 (Cole and Yonkers, 1995 Baldessarini, 1996). 

Efficacy in short-term treatment. From studies in adult schizophrenia, it is evident that clozapine treatment has at least the same or superior antipsychotic effect, compared to typical antipsychotics. In some studies, clozapine was superior with regard to symptom reduction in severe and acute schizophrenic patients. As the guidelines do not allow the use of clozapine as a first-choice drug, most patients have been treated before with at least two atypical or typical antipsychotics. Only one controlled trial has assessed the efficacy of clozapine in child and adolescent psychiatry. In this study (Kumra et ah, 1996), clozapine was found to be superior to haloperidol in all measures of psychosis, and showed a striking superiority for both positive and negative symptoms. 

Atypical Antipsychotic Effects in Schizophrenia. Molecular Psychiatry 12 (2007) 934-945. Kaddurah-Daouk and colleagues sampled the blood of 50 schizophrenia patients before and after drug treatment and found differences in metabolites that depended on the drug the patient received. 

Antipsychotic medications antagonize dopamine, which is believed to contribute to the antipsychotic effect of these medications. The atypical antipsychotics have other physiological properties as well, some of which appear to relate to antagonism of the serotonin type 2 (5-HT2) receptor, which may modify dopamine activity in a regionally specific manner. Dual 5-HT2 receptor-dopamine type 2 (D2) receptor antagonism is believed to account, at least in part, for the superior efficacy and more favorable side-effect profile of atypical antipsychotics. 

Second phase (duration about one week) the sedative effect recedes while the antipsychotic effect is retained during this phase, despite a pronounced reduction in emotional tension, there is still a danger of unexpected emotional outbreaks and over-reactions. 

Some 20 years later, Keck et al. (1989) noted that the course of action of neuroleptics, particularly the onset of their specific antipsychotic action, has still not been studied accurately enough. According to these authors there have been hardly any controlled studies in which clear distinction was made between the non-specific calming action and the antipsychotic effects of neuroleptics. 

Looking back on it today, it would seem that chance played a smaller role in the discovery of the antidepressant effect of imipramine. The antimanic effect of lithium had already been recognized although lithium was only being used in a few clinics and the recently discovered antipsychotic effect of... 

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 ... 

The administration of biological precursors of serotonin, which can be converted to serotonin in the CNS, was found to have no clear-cut antipsychotic effect in acute schizophrenic patients (in contrast to what had been predicted by Woolley and Shaw). 

Antipsychotic effect. In schizophrenic patients, they improve thought disorders, blunted affect, withdrawal and self centered behaviour. They also improve the hallucinations and delusions. 

The revolutionary idea that drugs could exert a specific antipsychotic effect, coupled with a growing recognition of their significant drawbacks, led to the search for other substances with similar beneficial properties and fewer adverse effects. Thus, pharmacological animal screens, followed by systematic clinical investigations with chemically or structurally related compounds, has led to a variety of effective, better tolerated drugs for schizophrenia and other major psychotic disorders. 

Other drug effects that decrease DA activity also support this position. Thus, when DA synthesis is blocked by a-methyl- p-tyrosine (AMPT), the dose necessary for an antipsychotic effect is reduced (i.e., the dose-response curve is shifted to the left by the interaction between dopamine and AMPT). A drug such as reserpine that can deplete DA stores also has relatively mild antipsychotic properties. Also, aripiprazole, which has D 2 presynaptic agonist properties, decreases the production of DA, as well as blocking D2 postsynaptic receptors. 

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