Antischizophrenic drugs

Hong, J. S., Yang, H.-Y. T., Fratta, W., and Costa, E. (1978) Rat striatal methionine-enkephalin content after chronic treatment with cataleptogenic and non-cataleptogenic antischizophrenic drugs. J. Pharmacol. Exp. Ther., 205 141-147. 

Creese, I., Burt, D.R., Snyder, S.H. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192. 481-483. 1976. 

Burt, D. R., Creese, I., Snyder, S. H. 1977, Antischizophrenic drugs chronic treatment elevates dopamine receptor binding in brain, Science, vol. 196, no. 4287, pp. 326-328. 

Although the prevailing concept is that schizophrenia is due to hyperdopaminergic activity in the CNS,, not all antischizophrenic drugs act as DA antagonists some instead modify serotonin function. -... 

Hong JS, Yang H-YT, Costa E (1978a) Substance P content of substantia nigra after chronic treatment with antischizophrenic drugs. Neuropharmacol, 17, 83-85. 

The prefrontal cortex (PFC) is thought to integrate cognitive and emotional functions and, as the target area for the mesocortical dopamine system, may be the primary dysfunctional area in schizophrenia and the site of action for antischizophrenic drugs (Thierry et al., 1978). This area is also exquisitely responsive to stress (Thierry et al., 1976), and it is well established that schizophrenia... 

Creese I and Snyder S, H. (1977) A simple and sensitive radioreceptor assay for antischizophrenic drugs in blood Nature 270,ISO-182. 

Costa E., Cheney D L., Mao C. C., and Moroni F (1978) Action of antischizophrenic drugs on the metabolism of 7-ammobutyric acid and acetylcholine m globus pallidus striatum and n. accumbens Fed Proc 37, 2408-2414... 

Freedberg, K. a., Innis, R. B., Creese, I., and Snyder, S. H., 1979, Antischizophrenic drugs differential plasma protein binding and therapeutic activity. Life Sci. 24 2467—2474. 

Snyder, S., Greenberg, D. and Yamamura, H. 1. (1974) Antischizophrenic drugs and brain cholinergic receptors. Affinity for muscarinic sites predicts extrapyramidal effects. Arch. gen. Psychiat., 31,58. 

Figure 7.17 The antischizophrenic drug thioridazine is oxidized metabolically on the methyithio group to a suifoxide and this is further oxidized to a methyi suifone. Oxidation aiso occurs on the phenothiazine suifur to form a suifoxide.

Chlorpromazine had been shown to produce a tranquil state in animals and since it had a similar effect in humans it became known as a major tranquiliser but the term is rarely used today. Sometimes the drugs used to treat schizophrenia are called anti-psychotics but more commonly neuroleptics. Leptic means to activate (take hold of) and in animals these compounds produce a state of maintained motor tone known as catalepsy. This is an extrapyramidal effect and in schizophrenics the neuroleptics can cause a number of extrapyramidal side-effects (EPSs) including Parkinsonism. The new term neuroleptic is unsatisfactory as a description of clinically useful drugs. It really describes a condition (catalepsy) seen in animals and is more indicative of a compound s ability to produce EPSs than to treat schizophrenia. Antipsychotic is more descriptive but could imply a more general efficacy in psychoses than is the case. It would seem more appropriate to call a drug that is used to treat schizophrenia an antischizophrenic just as we use the terms antidepressant or antiepileptic irrespective of how the drug works. Despite such personal reservations, the term neuroleptic will be used in this text. 

The slow time-course of depolarisation block not only offers an explanation for the latency of action of neuroleptic drugs but its occurrence may explain how they actually reduce DA function. Whether it explains their antischizophrenic effect is less certain since it is not possible to determine if such depolarisation occurs in patients on neuroleptic drugs. Certainly if this is how neuroleptics work it cannot be claimed that they have returned brain function to normal. 

In deciphering the role of the different NTs, or more precisely their antagonists, in the antischizophrenic action of neuroleptic drugs it must be remembered that published binding data and calculated dissociation constants vary considerably, which, of course, affects correlation coefficients made with clinical activity. Factors to bear in mind are ... 

The antischizophrenic actions of these drugs may not consist simply of postsynaptic blockade of hyperactive dopamine systems. Such a blockade occurs within hours, while most symptoms improve over weeks. This discrepancy in the latency to therapeutic effect has been hypothesized to be linked to drug-induced changes in dopaminergic activity after initiation of therapy, dopamine turnover increases, but after continued antipsychotic treatment, tolerance develops and dopamine metabolism returns to normal. This downward adjustment of dopaminergic activity is consistent with the decreased plasma concentrations of the dopamine metabolite homovanillic acid, an observation that correlates temporally with the clinical response to drug treatment. 

Thiepanes of the general structure (256) include the drugs octoclothepin (antischizophrenic), chlorotepin (antiinflammatory), trifluthepin (antidepressant), methiothepin (antihistamine) and oxyprothepin (neuroleptic). The slightly modified 10,11-dihy-drodibenzo[6,/]thiepins (257 dithiadene) and (258) have a similar range of pharmacological activities. 

It is not clear that so-called antipsychotic drugs are superior to other types of drugs with sedative effects but different mechanisms of action. Lithium, benzodiazepines and opium have been shown to be comparable to neuroleptics in the treatment of psychotic states in some studies. The ability of the neuroleptic drugs to reduce the most characteristic symptoms of psychosis such as hallucinations, delusions and thought disorder have often been interpreted as evidence of their specifically antipsychotic or antischizophrenic action (The National Institute of Mental Health Psychopharmacology Service Center Collaborative Study... 

Pioneers in the field recognized and wrote about the lobotomy-like effects of the neuroleptic drugs when they first came into use, but in recent years drug advocates have promoted the false impression that these medications have a specific antipsychotic or antischizophrenic effect. In reality, the overriding clinical effect of these highly toxic chemical agents is to render patients and inmates more emotionally flat and indifferent, more apathetic and docile, and less autonomous and self-directed. 

Horn, A.S. and Synder, S.H. (1971) Chlorpromazine and dopamine. Conformational similarities that correlate with the antischizophrenic activity of phenothiazine drugs. Proc. Natl Acad. Scl USA 68 2325-2328. 

Fig. 22.5. Conformations of chlorpromazine (A), dopamine (B), and their superposition (C) as determined by x-ray crystallographic analysis. The a, b, and c in (A) designate rings. Also shown (D) is another conformation in which the alkyl side chain of chlorpromazine is in the trans conformation (ring a and amino side chain), which is not superimposable on to dopamine. (Adapted from Horn AS, Snyder SH. Chlorpromazine and dopamine Conformational similarities that correlate with the antischizophrenic activity of phenothiazine drugs. Proc Natl Acad Sci U S A 1971 68 2325-2328 with permission.)...

Crow.T. J. and Gillbe, C. (1972) Dopamine antagonism and antischizophrenic potency of neuroleptic drugs. Nature New Biol., 245, 27. 

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