Clozapine action

PET studies show that at effective therapeutic plasma concentrations most neuroleptics occupy some 80% of brain Dj receptors (in the striatum at least) and this is therefore considered to be a requirement for efficacy (Pilowsky, Costa and Eli 1992 Farde 1996). If that is so then clozapine, which occupies only 20-40% of the Dj receptors at a therapeutic concentration, must have some other action which accounts for its therapeutic effectiveness. 

Some neuroleptics, including clozapine, are potent 5-HT-receptor antagonists and the possible role of 5-HT in the action of neuroleptics and the development of schizophrenia has recently generated much interest (Busatto and Kerwin 1997). This has centred primarily on 5-HT2A receptors found in the limbic cortex, which are linked to neuronal excitation and believed to mediate the hallucinogenic effects of drugs such as lysergic acid diethylamide (LSD). 

Many of the neuroleptics are a-adrenoceptor antagonists. Some, like chlorpromazine, block d postsynaptic receptors while clozapine (and risperidone) are as potent at 2 as D2 receptors. There is no evidence that either of these actions could influence striatal or mesolimbic function but NA is considered important for function of the prefrontal cortex and any increase in its release, achieved by blocking a2-mediated autoinhibition, might contribute to a reduction in negative symptoms and provide a further plus for clozapine (see Nutt et al. 1997). Centrally, however, most a2-receptors are found postsynaptically and their function, and the effect of blocking them, is uncertain. 

Certainly clozapine can avoid EPSs by only blocking a fraction of D2 receptors but that seems insufficient on its own to make clozapine so effective in schizophrenia. That is probably achieved by a unique combination of other blocking actions, at Di, D4, 5-HT2, o 2 and possibly other receptors (see Fig. 17.8). It may simply be that clozapine is so effective because it is so dirty , a view held for many years about the first neuroleptic chlorpromazine. Indeed it is unlikely that the varied symptoms of such a complicated disorder could be rectified by manipulating just one NT. 

Whether the amelioration of negative symptoms results from an action in the cortex and, in particular, the prefrontal cortex requires further study. The fact that clozapine, the atypical drug that is currently most effective in this respect, has actions there which are not shown by other compounds is encouraging even though the precise mechanism by which it works remains to be elucidated. 

Dopamine receptor blocking agents. Many of the neuroleptics used in the treatment of schizophrenia frequently produce parkinsonian symptoms as unwanted effects. Neuroleptics block dopamine receptors and their therapeutic effect seems to be related to this action. Although these drugs act on DA systems without distinction, some are more selective. Thioridazine, clozapine and molindone, for example, have electrophysiological effects in the limbic region of the brain but little action in the nigro-striatal area. This selectivity may be related to receptor subtype specificity (see Chs 12 and 54). 

Therefore, we believe that this alone is not a sufficient definition for atypicality. We prefer to define atypical antipsychotics as those that are less prone to causing EPS because they work differently than the typical antipsychotics. This, of course, raises the question of just how these medications work. Using clozapine as the starting point to answer this question has proved difficult. Why The problem is that clozapine interacts with so many different types of nerve cell receptors that it becomes hard to tell which of these actions makes the difference. 

Detailed studies of the binding of H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the Di receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor conversely, the receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appears to have a high affinity for most therapeutically active neuroleptics. 

Clozapine is a neuroleptic, which expresses antipsychotic and sedative action. It does not cause general depression and extrapyramidal disorders. It is used for severe and chronic... 

All antipsychotics except clozapine and perhaps olanzapine produce hyperprolactinemia by removing the inhibitory actions of dopamine on prolactin secretion. This results in amenorrhea, galactorrhea, and infertility in women and in loss of libido and impotence in men. Inhibition of the release of follicle-stimulating and luteinizing hormones may also play a role. In addition, weight gain is common, and food intake must be monitored. 

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