Schizophrenia neuroleptic side effects

Despite the efficacy of the typical neuroleptics such as chlorpromazine and haloperidol in treating the acute symptoms of schizophrenia, their side effects and failure to treat the negative symptoms emphasized the need to develop atypical antipsychotics. The desirable features of a new antipsychotic are shown in Table 11.5. 

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. 

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 ...

Many DA receptor antagonists (neuroleptics) for treating psychoses (for example, schizophrenia) have become efficient medicines. However, most of them induce severe extrapyramidal side-effects (EPS) akin to parkinsonian symptoms and also, more seriously, they induce tardive dyskinesias (TD). There is a need for improvements in the neuroleptics in the clinic. The substituted benzamides are D2 antagonists, some of which display a high degree of limbic selectivity. Such a regional selectivity has been suggested to be beneficial from the side-effects point of view [11,12]. 

Molindone is a more active antipsychotic than chloropromzine. Its sedative effect is less expressed. Side effects are also expressed less than with powerful neuroleptics. It facilitates the reduction of spontaneous movements and aggressiveness, and is used for treatment of psychotic disturbances, particularly in cases of chronic and severe schizophrenia. A synonym of this drug is moban. 

Kumra, S., Jacobsen, L.K., Lenane, M., Smith, A., Lee, P., Malanga, C.J., Karp, B.I., Hamburger, S., and Rapoport, J.L. (1998a) Case series spectrum of neuroleptic-induced movement disorders and extrapyramidal side effects in childhood-onset schizophrenia. J Am Acad Child Adolesc Psychiatry 37 221-227. 

Atypical neuroleptics. Because of the limited effectiveness and safety of conventional neuroleptics in TS, clinicians have turned to a new generation of neuroleptics that have been introduced for the treatment of schizophrenia. Risperidone, a member of a class of antipsychotics that blocks both DA and serotonin receptors, has been established as superior to placebo and equal, or superior, to haloperidol in the treatment of schizophrenia (Chouinard et al. 1993 Marder and Meibach 1994]. Risperidone has a more favorable side-effect profile than that of conventional neuroleptics and may have less potential for producing tardive dyskinesia. Compared with haloperidol, fewer extrapyramidal side effects are observed with risperidone in doses of 6 mg/ day or less. As encouraging reports appear in the literature (Lombroso et al. 1995 Stamenkovic et al. 1994 van der Linden et al. 1994], risperidone is currently being widely used by clinicians to treat tic disorders. 

Pimozide is FDA-labeled for Tourette s disorder and is particularly interesting in that it is a highly specific DA antagonist that may produce fewer adverse effects than haloperidol. In open studies with adequate doses, this agent has demonstrated efficacy for acute schizophrenia. Several double-blind trials comparing pimozide with other neuroleptics also found it to be an equally effective maintenance therapy ( 34, 35, 36, 37 and 38). We consider this agent to be as effective as the other standard agents, with the same, but perhaps less severe, side effects. 

The atypical neuroleptics—or new generation neuroleptics—cause fewer adverse side effects, are more effective in managing the symptoms of schizophrenia, and are effective for the treatment of bipolar disorder with or without psychosis. However, these drugs are cost more than the older medications. The five approved in the United States as of 2002 are ... 

An important breakthrough in the development of novel neuroleptics arose over 25 years ago with the discovery of the dibenzazepine neuroleptic clozapine. This neuroleptic was novel because it attenuated both the positive and negative symptoms of schizophrenia without causing extrapyramidal side effects or elevating serum prolactin concentrations, effects which characterize most typical neuroleptics such as chlorpromazine and haloperidol. 

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. 

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 histaminel 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... 

Regarding the extrapyramidal side effects commonly found after treatment with the "classical neuroleptics, PET studies of schizophrenia patients have shown that such drugs occupy 70-80% of D2 receptors in the basal ganglia at therapeutic doses. It has been calculated that a D2 receptor occupancy in the basal ganglia of approximately 80% carries a high risk that the patient will develop extrapyramidal side effects. Furthermore, Canadian studies have shown that the occurrence of extrapyramidal side effects was a major predictor for the subsequent development of tardive dyskinesia. 

In CONCLUSION, the use of the "classical" neuroleptics, as exemplified by the phenothiazines, thioxanthines, butyrophenones and diphenylbutyl-piperidines, has been a landmark in the pharmacotherapy of schizophrenia and psychotic disorders. The efficacy of such drugs in the alleviation of the symptoms of schizophrenia is universally accepted. However, it is also evident that they have a spectrum of adverse effects that frequently renders their long-term use problematic. Side effects such as akathisia, Parkinsonism, tardive dyskinesia and the all too frequent changes in peripheral autonomic activity are largely predictable from the structure of the molecules and the basic animal pharmacology data. Such adverse effects, and the difficulties encountered when attempting to reduce their frequency and severity by concurrent medication, has stimulated the development of "atypical" neuroleptics such as clozapine and risperidone which, hopefully, will combine efficacy with a reduction in side effects. 

Chlorpromazine, the first modern drug to be used in the treatment of schizophrenia and other psychotic disorders, was introduced into psychiatry in 1952 [61]. It was followed by a number of other drugs for the treatment of these conditions (e.g., haloperidol, thioridazine). These were also called neuroleptics because of their neurological side effects, such as parkinsonian syndrome and tardive dyskinesia. Tardive dyskinesia is a movement disorder characterized by involuntary movements of the face and limbs. The antipsychotic properties of these drugs were inseparable from the extrapyramidal effects. 

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