Atypical neuroleptics

Eleven (9%) of the children developed TD, compared to 0% in a matched control group (p =. 003). The TD rate was particularly high among African American children (15%). Given the relatively short period of exposure, these rates are astronomically high and should discourage any attempts to give neuroleptics, atypical or not, to children. 

Robert G, Kennedy P (1997). Establishing cost-effectiveness of atypical neuroleptics. Br J... 

Dailey, JW (1992) Typical and atypical neuroleptic drug effects on dopamine and other neurotransmitter functions in rodents. PhD thesis, University of London, p. 125. 

Reference has been made already to the shortcomings of the term neuroleptic . We now have a situation in which the drugs that are most useful in schizophrenia are regarded as atypical. While the term was introduced to cover those neuroleptics that do not cause EPSs, it has become synonymous with clozapine which has additional advantages over other neuroleptics (e.g. reduces negative symptoms, see text). Thus it is not always clear what is meant or covered by atypical. Hopefully this distinction between the neuroleptics will become unnecessary as better compounds are developed and the older ones become obsolete. 

Second, although typical neuroleptics produce depolarisation block of both A9 and AlO neurons, the atypical neuroleptics only induce it in AlO neurons (Chiodi and Bunney 1983). So after an atypical neuroleptic the A9 neurons of the nigrostriatal tract remain functional, which would explain why EPSs are not seen. Another difference is seen with the expression of an immediate-early gene, c-fos, and although its functional significance is not clear, typical neuroleptics induce its protein production in both the striatum and nucleus accumbens while the atypicals only achieve it in the accumbens. 

There is certainly evidence that whereas typical neuroleptics are equally active in mesolimbic/cortical areas as well as the striatum, the atypical drugs are much less effective in the latter. This has been shown by (1) increased DA turnover through DOPAC and HVA production in vitro, (2) augmented DA and DOPAC release by microdialysis in vivo and (3) increased c-fos- ike, expression. 

How the atypical neuroleptics achieve this differential effect is less clear but they could achieve some control of schizophrenia without producing EPSs by ... 

Generally most atypical neuroleptics have higher affinity for 5-HT2 than D2 receptors while typical ones retain a preference for the D2 receptor. There is, however, no infallible separation since chlorpromazine (typical neuroleptic) is more active at 5-HT2A... 

Figure 17.7 Possible mechanism by which atypical neuroleptics with antimuscarinic activity produce few EPSs. Normally the inhibitory effects of DA released from nigrostriatal afferents on to striatal neuron D2 receptors is believed to balance the excitatory effect of ACh from intrinsic neurons acting on muscarinic (M2) receptors (a). Typical neuroleptics block the inhibitory effect of DA which leaves unopposed the excitatory effect of ACh (b) leading to the augmented activity of the striatal neurons and EPSs (see Fig. 15.2). An atypical neuroleptic with intrinsic antimuscarinic activity reduces this possibility by counteracting the excitatory effects of released ACh as well as the inhibitory effects of DA (c). Thus the control of striatal neurons remains balanced...

Functional activity (clinical effect, catalepsy in animals, etc.) is invariably correlated with plasma concentrations whereas the brain levels of many neuroleptics, which are very lipophilic compounds, could be much higher. Some clinicians also believe that many newer compounds achieve atypical status compared with older ones because they are used at minimal dosage while older ones are prescribed at established levels which may be unnecessarily high. 

What is obvious from all the experimental evidence is that it is easier to unravel the cause of the undesirable than it is to explain the desirable effects of neuroleptic drugs. EPSs occur because such drugs all have some D2 antagonist activity and so reduce DA transmission in the striatum. The degree to which they achieve this and whether they are typical or atypical depends on their affinity for D2 striatal receptors, since EPSs... 

Measuring the expression of the early-immediate gene c-fos supports the striatal role of neuroleptics in the induction of EPSs because although all neuroleptics induce such expression in both the nucleus accumbens and striatum, the atypical neuroleptics do so more in the accumbens while clozapine, but not risperidone, also achieve it in the prefrontal cortex (Robertson, Matsumura and Fibiger 1994). How this arises is uncertain but since risperidone is a more potent 5-HT2 antagonist than clozapine, it cannot be through that mechanism. 

Figure 17.9 Schematic representation of the proposed activity profile of an ideal neuroleptic. The figure shows DA pathways to the prefrontal cortex, mesolimbic nucleus accumbens and striatum the effects required for an ideal drug on the DA influence and symptoms there and to what extent they are met by most typical and atypical neuroleptics and by clozapine. Note that while all atypical neuroleptics induce few extrapyramidal w side-effects (EPSs) few of them, apart from clozapine, have much beneficial effect in overcoming negative symptoms of schizophrenia ...

Farde, L, Wiesel, FA, Nordstrom, AL and Sedvall, G (1989) Dj and D2 dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology 99 (Suppl) 528-531. 

Seeman, P (1990) Atypical neuroleptics role of multiple receptors, endogenous dopamine and receptor linkage. Act. Psychiatr. Scand. 82 (Suppl. 358) 14-20. 

Roberts, D.C.S., and Vickers, G. Atypical neuroleptics increase selfadministration of cocaine An evaluation of a behavioral sereen for antipsychotic activity. Psychopharmacology 82 135-139, 1984. 

Roberts D., Vickers G. Atypical neuroleptics increase self-administration of cocaine an evaluation of a behavioral screen for antipsychotic activity. Psychopharmacology. 82 1135, 1984. 

Table 11.4 shows that clozapine has approximately 10 times higher affinity for the D4 and 5-HT2A-receptors than the D2-receptor and shows a greater occupancy of the 5-HT2 than the D2-like receptors. The other atypical neuroleptic risperidone has a similar affinity for the two D2-like receptors but an affinity for the 5-HT2a-receptor that is just over 3 times lower than for the D2-receptor. Receptor occupancy in vivo shows a similar profile to clozapine. In contrast, haloperidol s affinity for the D4-receptor is just under 3 times lower and over 100 times lower for the 5-HT2a-receptor, with no binding to the latter in vivo. The fractional occupancy of striatal... 

Moller H-J (2000). Definition, psychopharmacological basis and clinical evaluation of novel/ atypical neuroleptics Methodological issues and clinical consequences. World Journal of Biological Psychiatry, 1, 75-91. 

Bantick RA, Deakin JFW and Grasby PM (2001). The 5-HTia receptor in schizophrenia Promising target for novel atypical neuroleptics. Journal of Psychopharmacology, 15, 37-46. 

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