Schizophrenia neuroleptics

Jeste, D., Lacro, J., Gilbert, P., Kline, J., 6c Kline, N. (1993). Treatment of late-life schizophrenia with neuroleptics. Schizophrenia Bulletin, 19, 817—830. 

Schizophrenia is perhaps the most debiUtating psychiatric illness in modem medicine, affecting about 1% of the general population. Many of those affected require institutionalization (180). Unfortunately, the compounds available to treat this disorder are not hiUy effective in treating the spectmm of symptoms in all patients. Adverse effects are also a problem (181). In addition, available antipsychotic (neuroleptic) dmgs (Table 5) can at most only provide symptomatic rehef. 

Major tranquilizer. A drug useful in the control of schizophrenia. Also referred to as neuroleptic or antipsychotic. 

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

Petrakis IL, O Malley S, Rounsaville B, et al Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia. Psychopharmacology (Berl) 172 291-297, 2004... 

Meltzer FiY, Cola P, Way L, et al (1995). Cost effectiveness of clozapine in neuroleptic-resistant schizophrenia. Am J Psychiatry 150, 1630-8. 

Kopala LC, Fredrikson D, Good KP, Honer WG (1996). Symptoms in neuroleptic naive first episode schizophrenia response to risperidone. Biol Psychiatry 39, 296-8. 

Displacement studies with a wide range of neuroleptics showed good correlation with their clinical potency in schizophrenia. 

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. 

If effective neuroleptics are DA antagonists, is there any evidence for increased DA function in schizophrenia ... 

Before trying to determine how the neuroleptics may reduce some of the symptoms of schizophrenia through modifying NT function it is necessary to consider ... 

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. 

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

Its activity at Di receptors has been put forward as a possibility and although it has a relatively higher affinity for Di than Dj receptors, compared with typical neuroleptics, it is still a weak antagonist at both and in the absence of evidence for Di (or D5) receptor involvement in schizophrenia the significance of any Di antagonism is unclear. 

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). 

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. 

On this evidence one can confidently equate EPS with neuroleptic DA receptor (D2) antagonism in the striatum and possibly a reduction in the positive symptoms of schizophrenia through similar action in the limbic system (nucleus accumbens). 

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 ...

It appears that an ideal neuroleptic may need to reduce DA activity in the mesolimbic system (nucleus accumbens) to counter the positive symptoms of schizophrenia, increase it in the prefrontal cortex to overcome negative symptoms and have little or possibly no effect on it in the striatum so EPSs do not arise (Fig. 17.9). No wonder we still await the ideal drug. 

The close resemblance between schizophrenia and PCP-induced psychosis suggests that the behavioral effects produced by PCP might be useful as a model of psychosis. On this basis, most animal studies have examined the ability of various agents to modify PCP-induced hyperactivity and stereotypy. While some studies suggest that neuroleptics such as haloperidol (Castellani and Adams 1981 Garey et al. 1980), chlorpromazine, or clozapine (Freed et al. 

Collazo, Y. etal. (1996). Neuroleptic dosing in Hispanic and Asian Inpatients with schizophrenia. Mt Sinai. ]. Med., 63, 310-13. 

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