sign in sign up
<<
Home , Remoxipride

British Journal of Psychiatry (1994), 164, 141—148 Editorial

The New Atypical A lack of extrapyramidal side-effects and new routes in research

A. W. KERWIN

The recent introduction of remoxipride, , these effects, to allow action without and now has awakened interest in extrapyramidal side-effects (i.e. be atypical). the clinical psychopharmacology of atypical anti The simplest definition, then, is that an atypical psychotics. This editorial concerns pharmacological antipsychotic is an effective neuroleptic that does not mechanisms of these drugs and their relative clinical provoke catalepsy in rats or, in other words, has a efficacy. wide therapeutic ratio for its antipsychotic effects The clinical efficacy of was first and extrapyramidal side-effects, such that these are discovered in the early 1950s (see Reynolds, 1992, not seen at clinically effective doses. Early examples for review); subsequent therapeutic research has had include clozapine, and (Gerlach two main goals: to define the mechanism of efficacy; et a!, 1975; Kramer et a!, 1978). More recent intro and to increase the therapeutic ratio of the drugs ductions include the substituted , such as with respect to their extrapyramidal side-effects and remoxipride (Hogberg et a!, 1987) and (which is why they are termed ‘¿atypical'). most recently risperidone (Mertens, 1992). The first aim has been largely achieved, and it is The catalepsy test is an important paradigm non now clear that antipsychotic drugs exert their effects presumptive of a relevant mechanism, and thus has by blockade of D2 receptors (e.g. Creese been very useful in delineating a range of pharma et a!, 1976). However, blockade of D2 receptors cological mechanisms by which a drug can be also predicts extrapyramidal side-effects. Moreover, atypical. Thus, clozapine is atypical because of its negative symptoms generally do not respond to low propensity to block D2 receptors (Pilowsky et treatment with atypical antipsychotics. Therefore, a!, 1992), and thioridazine is atypical because of its efforts to produce atypical drugs have focused on high intrinsic antimuscariic activity (Miller & Hiley, either searching for an alternative site of action of 1974). The substituted benzamides are atypical a drug, or seeking more subtle ways of differentially because of low D2 affinity but effective because of blocking D2 receptors. high selectivity to the D2 family of receptors (Kohier eta!, 1992), and risperidone may be atypical because of a protective effect of high 5-HT2 blockade Defining the term ‘¿atypical' (Janssen et a!, 1988). Antipsychotics are screened for efficacy against a Despite this, recently there have been attempts to number of animal paradigms, including amorphine redefine the term ‘¿atypical'accordingto a putative induced stereotypy, amphetamine-induced hyper mechanism. This is confusing, and Nutt (1990) has activity, inhibition of intracranial self-stimulation, observed that the term is variably being used to and conditioned operant behaviour (Janssen & Van describe drugs that do not sedate or cause extra Bever, 1978; Fielding & Lal, 1978). These effects are pyramidal side-effects, drugs that do not cause mediated by mesolimbic dopamine (DA) receptors depolarisation blockade, drugs that block D1 rather (Kelly et a!, 1975). But such drugs also block DA than D2 receptors, or drugs that block serotonin receptors in the striatum (Sanberg, 1980), causing receptors. In order for empirical drug tests to open immobility-reduced exploratory behaviour, and up hitherto unconsidered avenues of research and catalepsy (the animal equivalent of Parkinsonism). drug development, it is important to adhere to the Typically, classic neuroleptics have a low ratio original, non-specific definition. Such screening between these effects, and animals become cataleptic without presupposition of a pharmacological sub at the same doses that also block mesolimbic systems. strate is a useful dragnet to finding novel mechanisms. Thus most , , and From a clinical standpoint, clinical atypicality would butylphenpiperidines provoke catalepsy at doses be defined by the low propensity to produce extra close to their presumed therapeutic dose. The pyramidal side-effects and tardive dyskinesia relative challenge is therefore to widen the ratio between to typical drugs like and chlorpromazine,

141

Downloaded from https://www.cambridge.org/core. 02 Oct 2021 at 06:23:42, subject to the Cambridge Core terms of use. 142 KERWIN

as well as the low propensity to induce akinesia and it has been suggested that there may be a D1 bias hyperprolactinaemic effects. in vivo. Measures of dopamine metabolites in freely moving animals give some support to a D1 preferential Pharmacology of individual atypicals action of clozapine in vivo (Imperato & Angelucci, 1988). Studies with immediate early gene markers of Clozapine synaptic activity do not support this (see later). Recently, the D2 receptor has been cloned and Clozapine is the archetypal antipsychotic developed sequenced, which led to the revelation of further and known to be non-cataleptogenic since the early genetic subdivisions of the D2 family, namely D3 l960s (Coward et al, 1989), and this is reflected in and D4 (Sokoloff et a!, 1992). Of these, the D4 its clinical profile as a highly effective antipsychotic receptor has a uniquely high affinity for clozapine (Kane et al, 1988) with a low propensity to produce (Van Tol eta!, 1991). In addition, these studies show extrapyramidal side-effects (Claghorn et a!, 1987). that the D4: D2 affinity ratio for clozapine is higher Clozapine is a relatively non-selective drug and it has than for any other antipsychotic. However, high proved difficult to pin down the reason for its affinity alone cannot indicate efficacy, and this is atypicality. a difficult hypothesis to test because of the low abundance and limited distribution (frontal cortex Effect on dopamine systems hippocampus) of this receptor species. It was originally thought that clozapine, like other Van Tol et al (1992) have found that there are atypicals, has a preferential effect on mesolimbic polymorphic forms of the receptor, with a variant rather than striatal dopamine systems (White & sequence (repeated severalfold) in an intracytoplasmic Wang, 1983). However, electrophysiological studies loop of the protein. The higher-fold repeats seem to show that firing rates in both mesolimbic and striatal have lower affinity for clozapine and low second dopamine neurons are equally affected by clozapine messenger coupling potential (Van Tol et a!, 1992). and in a similar manner to haloperidol (Rebec et a!, We have tried to test the relevance of clozapine 1980). Its non-cataleptogenic and low profile of action at D4 receptors by determining whether non extrapyramidal side-effects are probably a result responsivity is associated with higher-fold repeats. of its low affinity for D2 receptors. Thus clozapine In an initial study of 84 patients, we have found this only weakly displaces 3H- from D2 sites not to be the case (Shaikh et a!, 1993). It is also (Kohier et al, 1981). apparent that a relatively low-efficacy antipsychotic, This has been confirmed in vivo in patients. Farde loxapine, has even higher affinity for D4 receptors et a! (1992), using positron emission tomography, than clozapine. Thus the relevance of D4 receptors have determined a threshold for D2 occupancy by to clozapine's action remains unanswered. neuroleptic which predicts extrapyramidal side effects at about 80°looccupancy. Occupancies for Effect on 5-HT systems clozapine patients were only in the range 30—60%. This then is sufficient to account for its lack of extra Serotonin type-2 (5-HT2) receptors are also a strong pyramidal side-effects —¿buthow does it work? candidate for clozapine's antipsychotic action. Our group (Pilowsky et a!, 1992) demonstrated 5-HT2 receptors are highly enriched in medial pre that this low occupancy is not sufficient to account frontal cortex (a candidate region for the site of the for its clinical effect. In this study, it was shown neurochemical abnormality; e.g. see Weinberger, that a group of non-responders on classic anti 1987) and clozapine has very high affinity for these psychotics had high D2 occupancy and that a group sites in radioligand studies (Altar et a!, 1988). of clozapine responders had low D2 occupancy (two Clozapine also has potent effects on neuronal firing of the patients being scanned serially). Other rates when applied iontophoretically to medial pre candidates for clozapine's site of action then include frontal cortex (Ashby & Wang, 1990). In addition, not only D1, D4 5-HT2, but also muscarinic and a pure 5-HT2 antagonists have been reported as anti receptors. psychotic in open studies (Reyntjens et a!, 1986). Farde et a! (1992) have shown clozapine to have Neuroendocrine studies and metabolite studies on a higher occupancy at D1 receptors than classic anti 5-HT2-dependent responses suggest that clozapine psychotics, although in vitro studies show it to also has potent effects in vitro (Meltzer, 1989a). be a modest inhibitor of D1 binding. Moreover, Studies in patients have shown that high ratios of other relatively ineffective compounds have higher 5-HIAA over homovanillic acid retrospectively affinity for D1 sites (Andersen et a!, 1986), and predict good response to clozapine.

Downloaded from https://www.cambridge.org/core. 02 Oct 2021 at 06:23:42, subject to the Cambridge Core terms of use. ATYPICAL ANTIPSYCHOTICS 143

Meltzer (1989b) has argued that the unique profile preferentially displaces 3H- from limbic of clozapine relates to parallel effects of the drug on areas (olfactory tubercle and septum) as opposed to 5-FIT2 and DA2 systems. Most recently, however, striatal areas (Kohler eta!, 1992). Chronic treatment clozapine has also been recognised as having high with remoxipride, unlike with haloperidol, does not affinity at 5-HT1@(Canton et a!, 1990) sites, which produce behavioural supersensitivity. (A mesolimbic are also enriched in prefrontal cortex (Hoyer et a!, specific phenomenon; Ogren eta!, 1990). In addition, 1986).So there are other potential routes to clozapine's remoxipride fails to provoke D2 receptor super 5-HT-dependent effect, and the effect of clozapine on sensitivity and fails to induce D2-receptor dependent this complex receptor system needs to be fully mRNA and neurotensin changes in the striatum catalogued before any firm conclusions can be (Kohler et a!, 1991; Levant et a!, 1991). drawn. Remoxipride has very high selectivity at D2 re ceptors only. In vitro radioligand studies show it to Anatomica! studies have modest affinity at D2 receptors and negligible affinity for the D1 receptor (Hall et a!, 1986); it There has been immense interest in the study of also has virtually no potential to bind to 5-HT2, immediate early gene expression (c-fos and c-jun) as muscarinic or a adrenoceptors (Hall et a!, 1986). Its markers of synaptic activity, and gene expression has profile, therefore, is very different from that of been useful as a sensitive indicator of the anatomical clozapine, and the two drugs must have differing localisation of drug effects (e.g. Graybiel eta!, 1990). mechanisms for their atypicality. Studies with clozapine have been used to illuminate The pharmacology of remoxipride at the D2 their site of action and possibly help to determine receptor family is of interest. Although it has reason the receptor action relevant to its functional effects. able affinity for the D2 receptor (Malmberg et a!, Robertson & Fibiger (1992) have shown that, unlike 1993), it has very low affinities for the other haloperidol, clozapine fails to induce c-fos in the molecular members of that family, D3 and D4 striatum, but, like haloperidol, induces activity in (again unlike clozapine —¿Sokoloffet a!, 1992; Van the nucleus accumbens. Clozapine, however, is Tol et a!, 1991, 1992). Of particular interest is the unique in its ability to activate lateral septum and differential affinity of remoxipride for the long and medial prefrontal cortex. These effects were not short isoforms of the D2 receptor, it having an mimicked by D1 and D2 antagonists, and not order of magnitude higher affinity for the short form diminished by destruction of DA systems with (Malmberg et a!, 1993). Not enough is yet known 6-OHDA. Thus clozapine actions do not seem to be about the function and distribution of the long and mediated through dopamine systems. It remains short form of the D2 receptor to determine whether difficult to tie down the receptor system as prefrontal this confers the mesolimbic sensitivity to remoxipride, cortex does, but lateral septum does not, have 5-HT but it is clearly a possibility and, if so, may be a receptors. But certainly it indicates a unique useful screen for atypical drugs. anatomical profile independent of dopamine systems. The only other recognised high-affinity binding potential for remoxipride is at the sigma/ binding site of the glutamatergic non Remoxipride methyl-D-aspartate (NMDA) receptor (Hall et a!, In the l970s and 1980s, the continuing search for 1986). This may be of relevance, as there is now a atypical drugs produced the substituted benzamides glutamate hypothesis of schizophrenia (Meldrum & (e.g. sulpiride and remoxipride). Remoxipride has Kerwin, 1987) which is partly based on the psycho at least equal antipsychotic potency to haloperidol tomimetic potential of agents stimulating this site (Lewander eta!, 1990). it is indeed non-cataleptogenic (e.g. phencycidine). Behavioural studies also show in rats (Ogren et a!, 1990), and this is reflected in that remoxipride blocks phenylclidine-induced loco its low potential for extrapyramidal side-effects motion at theoretical antipsychotic doses (Ogren & (Morrison et a!, 1990). Goldstein, 1993). However, the sigma site can also The reason for its atypicality is difficult to under be associated with sites distinct from the combined stand. Substituted benzamides are selective and sigma/phencyclidine site of the NMDA receptor. potent D2 receptor blockers. Like clozapine, it was Therefore, further clarification is required. suggested that the drug might be site specific, and Studies of c-fos expression have also been per this may indeed be the case for remoxipride, as there formed for remoxipride (Deutch et a!, 1992). is much evidence that it preferentially effects a sub Remoxipride, like clozapine, does not activate the population of mesolimbic D2 receptors. Thus, in er dorsolateral striatum, but activates the ventral vivo autoradiography experiments, remoxipride striatum; however, unlike clozapine, it does not seem

Downloaded from https://www.cambridge.org/core. 02 Oct 2021 at 06:23:42, subject to the Cambridge Core terms of use. 144 KERWIN to activate medial prefrontal cortex or lateral septum. changes on serotomn function, suggest a complex To date there have been no functional neuroimaging interaction with risperidone of these dual systems studies with remoxipride detailing D2 occupancy in (Awouters eta!, 1990). These studies are difficult to patients. interpret, but in general they support the notion that Thus, whereas clozapine is a relatively non 5-FIT2 blockade compensates for some of the con specific, non-selective drug (and for which there are sequences of D2 blockade, particularly at higher several possibilities for its being atypical), re doses. This is highly relevant to the bell-shaped moxipride is highly selective to D2 receptors, and its clinical dose—responsecurve for risperidone (see atypicality may indeed be due to its superselectivity below). at subtypes of D2receptors, possibly the D2b (short At present there are no c-fos studies. There has form) of this receptor, localised within different been a limited study of subclinical (1 mg) doses of subsets of neuronal systems. 5-HT2 and D2 receptor occupancy in two volunteers using positron emission tomography. About 50°lo occupancy for both was seen at 1mg, predicting high Risperidone occupancy of both receptors in the clinical dose range Risperidone is the most recently introduced atypical, (Nyberg et a!, 1993). This high D2 occupancy ex having been launched in the UK in the summer of plains the extrapyramidal side-effects and akathisia 1993. Risperidone is again truly non-cataleptogenic with risperidone at higher doses. (Janssen et a!, 1988) with clear clinical efficacy for both positive and negative symptoms. Its atypicality is not fully translated into clinical practice, as Data from clinical trials troublesome dystonias and akathisias have been Clozapine described, but the drug does have a low propensity to produce Parkinsonism (Janssen Research There are two phases to the clinical trials of clozapine Foundation, 1988). for the efficacy and tolerability: the early phase, Risperidone is different again from clozapine or before its withdrawal; and later trials, which remoxipride, as it possesses high affinity and non stimulated its renaissance. In general, early trials selective receptor actions. Radioligand studies in vitro tended to use lower dose regimes. Clozapine was show it to have high affinity for 5-HT2 a adrenergic, originally introduced in 1966, and open-trial data D2 and histaminergic sites, modest affinity at other were published by Brezewski et a! in 1969. S-HTIACD receptors, and negligible affinity for D1 Subsequent multicentre trials with large numbers of and sigma sites(Schotte eta!, 1989;Leyseneta!, 1992). patients appeared from 1971 (Angst, 1979) in so Behavioural and peripheral markers of serotonin called productive and paranoid hallucinatory schizo and dopamine systems show a rather complex picture phrenia. Clozapine at 150—400mgwas as effective for risperidone. Its atypicality in the catalepsy test as high-potency neuroleptics such as chlorpromazine, (Janssen eta!, 1988)is obviously at odds with its high and superior to low-potency neuroleptics such as affinity for D2 receptors. Moreover, other indices of and thioridazine (Gross eta!, 1970). D2 activity, such as locomotion and food intake, At that time these trials noted that the drug was are only weakly antagonised by risperidone (Janssen virtually free from extrapyramidal side-effects, but eta!, 1988). There is no pharmacological explanation hypersalivation and hyperthermia were frequent. The for this. Therefore, one of the other potent effects excessive drowsiness noted for the drug was con of risperidone must be counterbalancing the D2 sidered as an advantage in acute cases, and it was effect, producing atypicality. This leaves the question even recommended that 10—25mgmay be useful as open as to whether risperidone's antipsychotic effect a hypnotic. In 1975, 16 patients of 3200 in Finland is at the D2 receptor or at another site. Both in vivo treated with clozapine developed agranulocytosis and in vitro studies point to a peculiarly high affinity (Amsler eta!, 1977; Idanpaan eta!, 1977), and four at 5-Hi'2 receptors (Janssen et a!, 1988) (the rele out of 2900 developed agranulocytosis in Switzerland, vance of this has been discussed under ‘¿Clozapine'leading to the drug's voluntary withdrawal. above). This is translated into powerful behavioural The drug remained available in some parts of the effects, as judged by sleep/wakefulness, and electro world, such as Germany, Denmark and Sweden, and encephalographic sleep studies over the theoretical the clinical experience of the usefulness of the drug clinical dose range (Dugovic et a!, 1989). in these countries has been documented. In Germany, Complex interactive behavioural studies of ris the usage of clozapine increased in the 1970s and peridone's effect on serotonin-induced changes in came to be anecdotally recognised as useful in up dopamine function, and on dopamine-induced to 70% of therapy-resistant states (Helmschen, 1989),

Downloaded from https://www.cambridge.org/core. 02 Oct 2021 at 06:23:42, subject to the Cambridge Core terms of use. ATYPICAL ANTIPSYCHOTICS 145 with the occasional dramatic improvements. In Remoxipride all cases, extrapyramidal side-effects were said to be diminished when patients were transferred to Remoxipride was introduced in the UK in 1989. The majority of clinical trials before its introduction were clozapine; over seven and a half years, relapse rates were reduced from 35% to 21°loperannum, and in against haloperidol in acute or acutely relapsed patients. The aggregate data are well summarised by 50% of cases there were no relapses during treatment (Pietzker & Stahl, 1988). Lewander et a! (1990). Six hundred and sixty-six patients received remoxipride, and 437 received In Sweden, a cohort of patients in Uppsala was halopendol. At daily doses of 150—600mg, re monitored from 1974 to 1978 (Lindstrom, 1988). moxipride had similar effects to 5-45 mg haloperidol, This study showed a 36% drop-out rate due to lack of efficacy, intolerability, and poor compliance. but with much fewer extrapyramidal side-effects. In some studies, the discontinuance rate on haloperidol Of the remainder, 36% were moderately improved was 50%. and 43% significantly improved; 39% regained In a study of relapse prevention, Walinder & Holm employment, while 10 of the 96 patients de veloped neutropenias, no extrapyramidal side-effects (1990) performed a six-month double-blind trial, followed by a further six-month open analysis of occurred. remoxipride versus haloperidol. This showed re In Denmark, the drug was relaunched in 1983, and moxipride to be similar to haloperidol, but with a long-term retrospective analysis (Povlsen et a!, much lower rates of emergent symptoms. A study 1985)showed that 51% of patients improved on being by Chouinord (1990) with placebo and chlor transferred to clozapine, 47% did not, and 2% grew as comparators showed remoxipride to worse. Again, occasional so-called ‘¿specialclozapine be superior only in those who were previous good responders' were noted, and it was anecdotally noted responders to neuroleptics. The most frequent side that young adults with early-onset illness usually fell effects in all the trials for remoxipride were akathisia, into this category. tremor and rigidity, but at rates of 50% less than These studies led to pressure in the USA for its re with equivalent doses of haloperidol. introduction, and a series of carefully conducted trials was performed. Claghorn et a! (1987) randomised Risperidone 151 patients, who had experienced extrapyramidal side-effects on at least two neuroleptics, to either Risperidone was introduced in 1993. There have been clozapine or chlorpromazine. Eleven patients on seven multicentre, double-blind trials against halo chlorpromazine continued to fmd the extrapyramidal peridol, and single trials against clozapine, per side-effects intolerable, and only one clozapine phenazine and levomepromazine. The trials were all patient experienced this. Scores on the Clinical similar, involving a somewhat short (one-week) Global Impression (CGI) scale and the Brief wash-out. Most trials involved a dose-finding Psychiatric Rating Scale (BPRS) showed clozapine protocol against a standard 20mg dose of halo to be superior to chlorpromazine, with hardly any peridol, followed by a six-week constant-dose period. extrapyramidal side-effects. Hypersalivation and The short wash-out and the fixed low-dose haloperidol sedation were the main adverse effects. Kane et a! may be responsible for some of the idiosyncratic (1988) took 319 patients refractory to three periods results, such as a worsening of the placebo group, of 1g chlorpromazine equivalents of two types of poor responses to haloperidol, and extrapyramidal neuroleptic and entered them into a trial of 60mg side-effects in the placebo group. Nevertheless, using haloperidol: 2% responded, and of the remainder, the BPRS, CGI, and the Scales for the Assessment 268 entered a trial of chlorpromazine versus of Positive and Negative Symptoms, there were clozapine. Of these, 38% of clozapine-treated impressive results for risperidone, with low scores patients compared with 5% of chiorpromazine for extrapyramidal symptoms. There is a bell-shaped treated patients responded, with greater than 20% response curve for risperidone, with maximal anti improvement in BPRS scores. The main adverse psychotic efficacy at 6—10mg, a dose which does not effects were drowsiness, salivation and fever. seem to provoke Parkinsonism, but in which there Clozapine was reintroduced in January 1990 in the were a number of akathisias and dystonias reported. UK and USA, with strict haematological monitoring, Drug-induced Parkinsonism is reported at higher for treatment-resistance or treatment-intolerant doses, but these doses are therapeutically ineffective, patients. Usage in general psychiatric practice suggests so this scenario should not develop. that one-third of patients improve dramatically; one These data are largely in the form of Janssen third derive significant benefit; and one-third do not technical reports, but a number of examples have respond (King & Mills, 1993). now been published (Svestka eta!, 1990;Claus, 1992).

Downloaded from https://www.cambridge.org/core. 02 Oct 2021 at 06:23:42, subject to the Cambridge Core terms of use. 146 KERWIN

In a study (unpublished technical document) of Atypical antipsychotics, because of the initial 4—8mg risperidone and 400 mg clozapine, the two empirical style of screening, always proved to have drugs were statistically indistinguishable. However, an unsuspected twist to their pharmacology, which this was with a small sample size, of 20 patients, with opened novel avenues to schizophrenia research. variable dosage of respiridone compared with a fixed Thus they have provided important clues to the dose of clozapine, and it is impossible to draw firm neuroanatomical localisation of schizophrenia and conclusions. Longer-term studies are under way in have helped to reformulate the dopamine hypothesis relapse prevention. of schizophrenia. Their unusual actions were the driving force behind the search for genetic sub Position statement divisions of the , and their subsequent pharmacology at these receptors has All new atypicals are probably at worst equi-effective reconciled some long-standing anomalies in the as classic antipsychotics and certainly superior in psychopharmacology of schizophrenia. their tolerability and side-effect profile, and the monitoring service for clozapine effectively neutralises the risk of adverse consequences to agranulocytosis. Using such drugs at the end of a clinical decision tree Acknowledgements because of their novelty probably militates against I am grateful to Dr Tom Fahy for checking the intelligibility of their optimal usefulness. There is probably sufficient the manuscript and to combined feedback from Astra and Sandoz, diversity of choice for them now, as a group, to who mutually agreed to check the balance and accuracy of the contents. replace classic antipsychotics in first onset and acute relapses from routine clinical practice. Were it not for agranulocytosis, clozapine would be the first choice. However, for this reason it is reserved References to treatment-resistant or treatment-intolerant cases, ALTAR, C. A., WASLEY, A. M., NEALE, R. F., et a/(l988) Typical and it is certainly the drug of choice here. and occupancy of D, and S. receptors: Patients probably should not be given prolonged an autoradiographic analysis in rat brain. Brain Research treatment with classic antipsychotics before con Bulletin, 16, 517-525. sidering clozapine. Remoxipride would seem to be AMSLER, H., LEERENHOVI, L., BARTH, E., et at (1977) Agranulo cytosis in patients treated with clozapine: a study of the Finnish a sensible first choice, as it is effective and well epidemic. Acta Psychiatrica Scandinavica, 56, 241—248. tolerated. It is also probably an excellent choice for ANDERSEN, D. H., NIELSEN, E. B., GRONVALD, F. C., et at relapsed patients who have previously responded to (1986) Some atypical neuroleptics inhibit ‘¿H-SCH-23390 classic antipsychotics and on whom one does not binding in vivo. European Journal of Pharmacology, 120, 143—144. want to inflict extrapyramidal side-effects. ANGST, J., BENTE, D., HEIMANN, H., et at (1979) Das Klinische The clinical trial data on risperidone does not seem Wirkungsbild von clozapine (Untersuchung mit dem Amp transparent enough to make firm recommendations, system). Pharmacopsychiatry, 4, 201—211. and so it may best be reserved as second line, since ASHHY, C. R., Jr & WANG, R. Y. (1990) Effect of antipsychotic drugs on 5-HT, receptors in the medial prefrontal cortex: remoxipride is considerably cheaper. There are no microiontophoretic studies. Brain Research, 506, 346—348. objective data to suggest risperidone offers any Aw0UTER5, F. H. L., NIEMEGERS, C. J. E., MEGENS, A. H. P., et advantages over remoxipride. at (1990) Functional interaction between serotonin @2anddopa In treatment difficulties, clozapine probably mine D2 neurotransmission as revealed by selective antagonism of hypersensitivity to tryptamine and . Journal of should be considered early, as illness duration can Pharmacology and Experimental Therapeutics, 254, 945—951. militate against neuroleptic response in general and BREZEWSKI, H., HELMCHEN, H., Hippius, H., et at (1969) Das clozapine response in particular (Kerwin & Lofts, klinische wirkungspektrum eines nenn dibenzodiazepin 1993). Because of clozapine's potential to improve derivatives. (W108/47 1854: chloi-l l-(4-methyl) -5- dibenzo-(b-c) (1,4) diazepine). Aizneimittel forschung, 19, social functioning, quality of life and negative 459—496. symptoms, earlier use could be considered for CANTON, H., vERRELE, L. & COLPAERT, F. C. (1990) Binding of particular patients. typical and atypical antipsychotics to SHTC and SHT2 sites. There are many other areas where the relative Clozapine potently interacts with 5HT1@ sites. European Journat of Pharmacology, 191, 93—96. merits of classic versus atypical antipsychotics need CHOUINARD, G. (1990) A placebo controlled clinical trial of further clarification, for instance: in the very remoxipride and chlorpromazine in newly admitted schizophrenic behaviourally disturbed patient, where sedation is a patients with acute exacerbation. Acta Psychiatrica Scandinavica, requirement; for relapse prevention; where there are 82 (suppl. 358), 111—120. CLAGHORN, J., HONIGEELD, G., ABIJZZAHAB, F. S., et at (1987) The compliance difficulties and depot is being risks and benefits of clozapine versus chlorpromazine. Journal considered; and in elderly patients. of Clinical Psychopharmacology, 7, 377—384.

Downloaded from https://www.cambridge.org/core. 02 Oct 2021 at 06:23:42, subject to the Cambridge Core terms of use. ATYPICAL ANTIPSYCHOTICS 147

COWARD, D. M., IMPERAT0, A., URWYLEF, S., et a! (1989) KANE, J., HONIGFELD,G., SINGER,J., ci a! (1988) Clozapine for Biochemical and behavioural properties of clozapine. Psycho the treatment of resistant schizophrenia: a double blind pharmacology, 99, 86—812. comparison versus chlorpromazine. Archives of Genera! CREESE,I., BURT, D. R. & SNYDER,S. H. (1976) Dopamine Psychiatry, 45, 789—796. receptor binding predicts clinical and pharmacological potencies KELLY, P. H., SEviouR, P. W. & IvEIts@, S. D. (1975) Amphetamine of antischizophrenic drugs. Science, 192, 481—483. and apomorphine responses in the rat following 6-OHDA lesions DEUTCH,A. J., LEE, M. C. & LADAROLA,M.J. (1992) Regionally of the nucleus accumbens septi and corpus striatum. Brain specific effects of atypical neuroleptic drugs on striatal c-fos Research,94, 507—522. expression: the nucleus accumbens shellas a focus of antipsychotic KERWIN, R. W. & Loris, F. J. (1993) Clozapine in the management action. Molecular and Cellular Neurosciences, 3, 332—341. of schizophrenia. British Medica! Journa!, 307, 199—200. Ducovic, C., WAQUIER,A.& J@w@issEi4,P.A. J. (1989) Differential Kwio, D. J. & MILLS, P. (1993) Clozapine: the Holywell experience effects of the new antipsychotic risperidone on sleep and wake with the first 24 patients. Irish Journal of Psychological fulness in the rat. Neuropharmacotogy, 28, 1431—1433. Medicine,10, 30—34. FARDE, L., WIESEL, F. A., STONE-ELANDER, S., et a! (1990) D2 KOHLER,C., HAGLUND,L., OGREN,5. 0., et a! (1981) Regional dopamine receptors in neuroleptic naive schizophrenic patients. blockade of neuroleptic drugs of in vivo ‘¿H-spiperonebinding Archives of General Psychiatry, 47, 213—219. in the rat brain. Relation to blockade of apomorphine induced NORDSTROM, A. L., WIESEL, F. A., et a! (1992) Positron hyperactivity and stereotypies. Journal of Neural Transmission, emission tomographic analysis of central D, and D2 receptor 52, 163—173. occupancy in patients treated with classical neuroleptics and DANIELLSON,A.,MAGNUSSON,0., eta! (1991) Biochemical clozapine: relation to extrapyramidal side effects. Archives of pharmacology of the atypical neuroleptic remoxipride. Schizo Genera!Psychiatry,49, 538—544. phrenia Research, 4, 311—328. FIELDIsic,S. & L,u., J. (1978) Behavioural actions of neuroleptics. RADESATER,A. C., KARLSSON-BOETHIUS,G.,et a! (1992) Handbook of Psychopharmacology, Vol. 10 (eds L. Iversen, Regional distribution and in vivo binding of the atypical anti S. Iversen & S. Snyder), pp. 91—128.NewYork: Plenum Press. psychotic drug remoxipride. A biochemical and autoradiographic GERLACH,J.(1991) New antipsychotics: classification efficacy and analysis in the rat brain. Journal of Neural Transmission, 87,49-62. adverse effects. Schizophrenia Bulletin, 17, 289—309. KRAMER, M., Rom, T., SALIS, P., et a! (1978) Relative efficacy of THARSEN,K.& Foy, R. (1975) Extrapyramidal reactions loxapine succinate and thioridazine hydrochloride in the and amine metabolites in cerebrospinal fluid drives haloperidol treatment of acute schizophrenia. Current Therapeutic Research, and clozapine treatment of schizophrenic patients. 23, 619—631. Psychopharmacology, 46, 341—350. LEVANT,B., BISSEI-rE,G., WIDERLOV,E., et a! (1991). Alterations GRAYBIEL,A. M., MORATELLA,R. & ROBERTSON,H. A. (1990) in residual brain neurotensin concentrations produced by atypical Amphetamine and induced drug specific activation of neuroleptic drugs. Regulatory Peptides, 32, 193—207. the c-fos gene in striosome-matrix compartments and limbic LEWANDER,T., WESTERBERGH,S. E. & MORRISON,D. (1990) subdivision of the striatum. Proceedings of the National Clinical profile of remoxipride - a combined analysis of a Academy of Science, USA, 87, 6912—6916. comparative double blind multicentre trial programme. Ada GROSS, H., HACKL, H. & KALTENBAECK, E. (1970) Results of a Psychiatrica Scandinavica, 82 (suppl. 358), 92—98. double blind study of clozapine and thioridazine. 7th CINP LEYSEN,J. E., GOMMERAN,W. E., EENS, A., et at (1992) The Congress, Prague. biochemical profile of risperidone. Journal of Pharmacology and HALL, H., SALLEMURK,M. & JURNINGE,E. (1986) Effects of Experimental Therapeutics, 24, 661—670. remoxipride and some related new substitute salicylamides on LINDSTROM, L. H. (1988) The effect of long term treatment with rat brain receptors. ActaPharmacotogica Toxicotogia, 58,61-70. clozapine in schizophrenia: a retrospective study of 96 patients HELMSCHEN, H. (1989) Clinical experience with clozapine in Germany. treated with clozapine for up to 13 years. Ada Psychiatrica Psychopharmacology, 99, 880—883. Scandinavica, 77, 524—529. HOGBERG, T., NORINDER, U., RAMSBY, S., et a! (1987) New selective MALMBERG,A., JACKSON,D. M., ERICKSSON,A., et a! (1993) dopamine D2 antagonists as neuroleptic agents: chemical and Unique binding characteristics of neuroleptic agents interacting theoretical considerations. Acta Pharmacotogica Suecia, 24, with human dopamine D2, D2Band D, receptors. Molecular 289—328. Pharmacology, 43, 749—754. HOYER, D., PAzos, A., PROBST, A., et a! (1986) Serotomn receptors MELDRUM,B. S. & KERWIN,R. W. (1987) Glutamate receptors and in human brain II. Characterisation and autoradiographic schizophrenia. Journal of Psychopharmacology, 1, 217—221. localisation of 5HTE and 5HT2recognition sites. Brain Research, MELTZER,H. Y. (1989a) Clozapine: clinical advantages and 376, 97—107. biological mechanisms in schizophrenia. In Schizophrenia: A IDANPAAN,H. J., ALHAVA, E., OLKINNORA,M., et a! (1977) Scientific Focus (ed. C. Tamminga). New York: Oxford Agranulocytosis during treatment with clozapine. European University Press. Journa!of Cilnica!Pharmaco!ogy,11, 194—198. (1989b) Clozapine: mechanism of action in relation to its IMPERATO,A. & ANGELUCCI,L. (1988) Effects of the atypical clinical advantages. In Recent Advances in Schizophrenia (eds neuroleptics clozapine and flupermapine on the in vivo dopamine A. Kales, C. N. Stefanos & J. A. Talbon). Heidelberg: Springer. release in the dorsal striatum and in the prefrontal cortex. MERTENS,C. (1992) Risperidone treatment in psychotic patients: (Abstracts of the XVIth CINP congress, Munich.) Psycho a combined analysis of the data of three open long term trials. pharmaco!ogy, 45, 780—789. Janssen Clinical Research Report 1992. Berse: Janssen Research JANSSEN,P. A. & VAN BEVER,W. F. M. (1978) Structure activity Foundation. relationships of the butyrophenones and . MILLER,R. J. & HILEY,C. R. (1974) Antimuscariic properties of In Handbook of Psychopharmacology, Vol. 10 (eds L. Iversen, neurolepticsand drug induced Parkinsonism. Nature, 248,596-597. S. Iversen & S. H. Snyder), pp. 1—36.NewYork: Plenum Press. MORRISON,D., ENGLUND,A., LAWRIE,V., et a! (1990) Safety NIexmoERs,C.J. E., Awoursas, F., eta! (1988)Risperidone: evaluation in both short-term and long-term treatment of a new antipsychotic with serotonin S@and dopamine D2 schizophrenia with remoxipride. Acta Psychiatrica Scandinavica, antagonistic properties. Journal of Pharmacology and 82 (suppl. 358), 164—169. Experimental Therapeutics, 244, 655—693. Nun, D. J. (1990) Specific anatomy, non-specific drugs: the JANSSENRESEARCHFOUNDATION(1990)Risperidone: Investigators' present state of schizophrenia. 5th Biennial Winter Workshop. Brochure. Berse: Janssen Research Foundation. Journa!of Psychopharmacology,4,171—175.

Downloaded from https://www.cambridge.org/core. 02 Oct 2021 at 06:23:42, subject to the Cambridge Core terms of use. 148 KERWIN

NYBERG, S., FARDE, L., ERIKss0N, L., et at (1993) 5HT, and D, c-fos expression in the forebrain: contrasting effects of dopamine receptor occupancy in the living human brain. haloperidol and clozapine. Neuroscience, 46, 3 15—328. Psychopharmacology, 110, 265—272. SANBERG, P. R. (1980) Haloperidol induced catalepsy is medicated OGREN, S. 0., FLORVALL, L., HALL, H., et at (1990) Neuro by post-synaptic dopamine receptors. Nature, 254, 472—473. pharmacological and behavioural properties of remoxipride in ScHorrE, A., DE BRUYCKERE,K., JANsSEN, P. F. M., et at (1989) the rat. Acta Psychiatrica Scandinavica, 82 (suppl. 358), 21—26. Receptor occupancy by ritanserin and risperidone measured using & GOLDSTEIN,M.(1993) Phencyclidine and MK8OI induced cx vivo autoradiography. Brain Research, 500, 295—301. hyperlocomotion are differentially mediated Neuropsycho SHAIKH, S., COLLIER, D., KERwIN, R. W., et at (1993) Dopamine pharmacology (in press). D, receptor subtypes and response to clozapine. Lancet, 341, 116. PIETZKER, A. & STAHL, H. P. (1988) Rezidiuprophylax S0K0L0FF, P., MARTRES, M. P., GIR0S, B., et at (1992) The third Behandlungss —¿trategieund katamestiche. Erhebungen bei dopamine receptor (D,) as a novel target for antipsychotics. perazin.langzeitpatienten. In Therapiemit Neuroteptica-parazin Biochemical Pharmacology, 43, 659—666. (eds H. Helmehen, H. Hippius & R. Tölle), pp. 149—152. SVESTKA, J., CE5KOVA, E., DYSAHEK, R., et at (1990) Double blind Stuttgart: Thieme. clinical comparison of risperidone and haloperidol in acute PILOwSKY, L., COSTA, D. C., ELI, P. J., et at (1992) Clozapine, schizophrenic and schizophrenic psychosis. Activitas Nervosa single photon emission tomography and D, dopamine receptor Super, 32, 237—238. blockade hypothesis of schizophrenia. Lancet, 340, 199—202. VAN Tot., H. H. M., BuNzow, J. R., GUAN, H. C., et at (1991) POVLSEN, J., N0RiNG, N., Foc, R., et at (1985) Tolerability and Cloning of the gene for human D4 receptor with high affinity therapeutic effect of clozapine: a retrospective investigation of for the antipsychotic clozapine. Nature, 350, 610—619. 216 patients treated with clozapine for up to 12 years. Acta Wu, C. M., GUAN, H. C., et at (1992) Multiple dopamine Psychiatrica Scandinavica, 71, 176—185. D, receptor variants in the human population. Nature, 358, REBEC, G. V., BASHORE, T. R., ZIMMERMAN, K. S., et at (1980) 149—192. Neostriatal and mesolimbic neurones: dose dependent effects of WALINDER, J. & HOLM, A. C. (1990) Experiences of long term clozapine. Neuropharmacotogy, 19, 281—288. treatment with remoxipride: efficacy and tolerability. Acta REYNOLDS, G. P. (1992) Developments in the drug treatment of Psychiatrica Scandinavica, 83 (suppl. 359), 8 1—84. schizophrenia. Trends in Neuroscience, 13, 116—121. WEINBERGER, D. R. (1987) Implications of normal brain develop REYNTJENS, A., GELDERS, Y. G., HOPPENEROUWERS, M. J. J. A., ment for the pathogenesis of schizophrenia. Archives of General et at (1986) Thymesthemic effects of ritanserin (R55667). Psychiatry, 44, 660—667. A centrally acting serotonin 5, blocker. Drug Development WHITE, L. & WANG, R. Y. (1983) Differential effects of classical Research, 8, 205—211. and atypical antipsychotic drugs on A9 and AlO dopamine ROBERTSON, G. S. & FIBIGER, H . C. (1992) Neuroleptics increase neurones. Science, 221, 1054—1057.

R. W. Kerwin, MA, PhD, MRCPsych,SeniorLecturer in Neuroscience, Consultant Psychiatrist, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF

(Received September 1993, accepted September 1993)

Downloaded from https://www.cambridge.org/core. 02 Oct 2021 at 06:23:42, subject to the Cambridge Core terms of use.