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> 1000

> 1000

The lower the number, the stronger the affinity for the specific neuroreceptor. Ki, inhibitory constant; NA, noradrenaline.

The lower the number, the stronger the affinity for the specific neuroreceptor. Ki, inhibitory constant; NA, noradrenaline.

system, thereby attenuating the psychotic symptoms of schizophrenia. Experimental studies also show that clozapine, and other novel atypical neuroleptics, have little effect on the activity of the nigrostriatal dopaminergic system which probably accounts for the low incidence of extrapyramidal side effects seen with these drugs. Clozapine and several other atypical neuroleptics are also potent inhibitors of 5-HT2 type receptors, particularly the 5-HT2A and 5-HT2c subtypes (see Table 11.6) and it has been postulated that their antipsychotic action combined with a low propensity to cause extrapyramidal side effects may be attributable to the antagonism of 5-HT2A receptors combined with an inhibition of mesocortical D2 receptors. The experimental evidence to support this view arises from findings that stimulation of 5-HT2A receptors enhances the synthesis and release of dopamine in the rat brain. Conversely 5-HT2A receptor antagonists reduce the stimulant effects of amphetamine, a drug that in high doses can produce symptoms not unlike paranoid schizophrenia, possibly due to its ability to release dopamine in the mesocortical and mesolimbic regions of the brain.

Partly as a result of the extensive experimental and clinical studies which have been carried out on clozapine in recent years there have been two major approaches to the development of atypical neuroleptics. The first approach has been to develop drugs which broadly simulate the pharmacological profile of clozapine but which lack the adverse haematological effects. Olanzapine is an example of a drug recently marketed in Europe and North America which is based on this principle. The second approach has involved targeting specific dopamine receptors located in the forebrain. Clearly the aim of such developments is to produce neuroleptics that attenuate both the positive and negative symptoms of schizophrenia without causing extrapyramidal side effects. This has largely been achieved with the introduction of several atypical antipsychotics.

Pharmacological profiles of some atypical antipsychotics

The atypical antipsychotics are divided into two major pharamacological groups, namely the multiple receptor antagonists, such as clozapine, olanzapine and quetiapine, and the more selective 5-HT2/D2 antagonists as exemplified by risperidone, sertindole, ziprasidone and zotepine. The benzamide antipsychotic amisulpride is the most selective antagonist for the D2/D3 receptors which presumably gives it the mesocortical selectivity of action with a minimal effect on the dopamine receptors in the basal ganglia.

Olanzapine, like clozapine, has a broad spectrum of action on dopamine, 5-HT, adrenergic, histamine1 and muscarinic receptors (see Table 11.6). While the precise significance is presently unclear, it is of interest that whereas clozapine binds with a high affinity to 5-HT6 and 5-HT7 receptors, olanzapine only shows a high affinity for 5-HT6 receptors.

Clinical studies have demonstrated that olanzapine has a similar profile to clozapine without causing agranulocytosis; preliminary studies also show that it does not cause extrapyramidal side effects or increase prolactin release. Olanzapine has recently been introduced for the treatment of mania.

Risperidone has been developed as a combined D2/5-HT2A receptor antagonist. In addition, it has a high affinity for 5-HT1A and 5-HT7 receptors. Whether such an effect has any relevance to its beneficial effects on the negative symptoms of schizophrenia, and lack of extrapyramidal side effects at moderate therapeutic doses, is unknown. An important advantage of risperidone over clozapine lies in its lack of antagonism of muscarinic receptors.

Remoxipride is a selective D2 antagonist with higher affinity for the D2s subtype of receptors. It has no affinity for 5-HT, adrenergic, muscarinic or histamine receptors but, unlike the other atypical neuroleptics, does bind to sigma receptors (see p. 453 for possible importance of sigma receptors).

In clinical studies, remoxipride has been shown to improve both positive and negative symptoms of schizophrenia and may have a place in the treatment of resistant schizophrenic patients. In addition such side effects as the neuroleptic-induced deficit syndrome, sedation and extrapyramidal side effects are apparently absent in patients treated with the drug.

Unfortunately, a few cases of aplastic anaemia have been reported which may be drug related. This has led to the untimely withdrawal of the drug from the European market.

Amisulpride. The ability of amisulpride to reduce the negative symptoms of schizophrenia has been explained in terms of its selective antagonism of the dopamine (D2) autoreceptors in the prefrontal cortex that results in an increased release of dopamine in that region. This effect is most pronounced in low therapeutic doses. Higher doses reduce the subcortical dopaminergic system thereby reducing the positive symptoms of the disorder, an effect that is similar to that seen with the typical neuroleptics. In clinical studies, the frequency of extrapyramidal side effects is significantly lower than with any of the traditional neuroleptics which may be explained by the fact that less than 70% of the D2 receptors in the basal ganglia are occupied even at the higher therapeutic doses.

Quetiapine. This has a somewhat similar pharmacological profile to clozapine and olanzapine due to its multiple receptor antagonists action. It has been shown to reduce both the positive and negative symptoms of schizophrenia and has a low frequency of extrapyramidal side effects.

Sertindole. This is structurally unique among the atypical neuroleptics in that it is an indole derivative with a high affinity for 5-HT2A, D2-like (D2, D3, D4) and also alpha-1 receptors. The antagonistic action on the 5-HT2 receptors probably accounts for its beneficial effects on negative symptoms. Sertindole was suspended from marketing a few years ago because of the rare occurrence of cardiac conduction defects. As the causal relationship of this adverse effect to the drug was never firmly established it is likely to be relaunched in the near future.

Ziprasidone is a high potency antagonist of 5-HT2 receptors and to a lesser extent to D2-like receptors. It also acts as an agonist at 5-HT1A receptors and blocks the reuptake of noradrenaline which gives it a potential anti-depressant as well as an antipsychotic profile. It has a slight antagonistic action on both histamine1 and alpha-1 receptors which might be associated with a sedative profile and also a possible hypotensive effect. Like the other atypical antipsychotics, ziprasidone has little action on the basal ganglia.

Zotepine, like ziprasidone, is a potent 5-HT2 antagonist which also reduces the reuptake of noradrenaline. Its side effects, sedation and postural hypotension, are attributable to its antagonistic action on histamine1 and alpha-1 receptors. Zotepine, which has not yet been marketed in Europe, may have a similar profile to ziprasidone and could be useful in the treatment of depression associated with schizophrenia. Because of the evident clinical superiority of the atypical antipsychotics over the traditional neuroleptics, the World Psychiatric Association Task Force has

Figure 11.7. Chemical structure of selected atypical antipsychotics.

Remoxipride Risperidone

Figure 11.7. Chemical structure of selected atypical antipsychotics.

recently recommended that these drugs should be the first-line treatment for schizophrenia.

The chemical structures of some of these atypical antipsychotics are shown in Figure 11.7. A comparison of the sites of action and clinical effects of typical neuroleptics and atypical antipsychotics is shown in Table 11.7.

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