Antischizophrenic

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 ... 

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. 

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. 

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

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. 

Investigators have attempted to assess the impact of antipsychotics on the cognitive and the behavioral disturbances characteristic of schizophrenia. The antipsychotics decrease typical, but nonspecific, positive symptoms such as hallucinations and delusions ( Table 5-4). Thus, labeling them as antischizophrenic agents is too restrictive inasmuch as they also benefit such disparate disorders as psychotic depression or mania, iate-onset paraphrenia, and organic-induced psychosis. As the symptoms reduced by neuroleptics are typical of psychosis in general, these agents are best conceptualized as a type of antipsychotic. 

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... 

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. 

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. 

In the second section of the volume, N-hclerocycles such as phenothiazines, phenoxazines, dihydropyridines, and related compounds are shown also to have interesting biological activity including antitumor activity, vermicide, antibacterial activity, and antischizophrenic activity (i.e. chlorpromazine of the phenothiazine family and its analogs). The activity of phenothiazine and compounds such as phenoxazines and related heterocycles, and also recent bioactive mesoionic heterocycles will be discussed. 

ANTIEMETIC. ANXIOLYTIC and ANTIPSYCHOTIC (antischizophrenic) properties. The N -Me derivative = mezacoprlde [inn], which has antiemetic properties, zacopride fumarate zacopride. zacopride hydrochloride zacopride. 

Fig. 1 Correlation between antischizophrenic potency and H-haloperidol binding (reprinted from Ref. 18. Copyright 1977 by the A.A.A.S.)...

H. C. Kimko, S. S. Reele, N. H. Holford, and C. C. Peck, Prediction of the ontcome of a phase 3 clinical trial of an antischizophrenic agent (qnetiapine fnmarate) by simnlation... 

Neurotensin (NT) had been postulated as a possible antischizophrenic target because of... 

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 dibenzodiazepine clozapine (Table 12-14, X = NH), which is an antischizophrenic, has been approved on a limited basis (1989). Its atypical properties are that it does not bind to DA receptors and, as a result, does not appear to cause extrapyramidal symptoms. It may even reverse tardive dyskinesia. Unfortunately, reports of a high incidence of agranulocytosis severely restricts its use to patients who are refractory to standard antipsychotic medications. Fluperlapine (Table 12-14) is currently being investigated as an alternative... 

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. 

Thus, it may be possible in the future to selectively target the various modulatory sites on the GABAa receptor to produce preferential pharmacological effects—for example, benzodiazepines that are anxiolytic without sedative effects, antischizophrenic agents that lack sedation and extrapyramidal side effects, and general anesthetics that do not alter respiratory and/or heart rates. 

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.)...

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... 

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