Drug Evaluation
Drugs 40 (5): 722-747, 1990 00 12-6667/90/00 11-0722/$13.00/0 © Adis International Limited All rights reserved. DREND2143
Clozapine
A Review of its Pharmacological Properties, and Therapeutic Use in Schizophrenia
Andrew Fitton and Rennie C. Heel Adis Drug Information Services, Auckland, New Zealand
Various sections of the manuscript reviewed by: M . Ackenheil, Psychiatric Hospital, University of Munich, Munich, Federal Republic of Germany; D.E. Casey, Psychiatric Service, Veterans Administration Medical Center, Portland, Oregon, USA; W. W. Fleischhacker, Department of Psychiatry, Innsbruck University Clinics, Innsbruck, Austria; I. Gerlach, St Hans Hospital, Roskilde, Denmark; G.A. Gudelsky, Department of Psychiatry, University Hospitals of Cleveland, Cleveland, Ohio, USA; H. Kaiya, Department of Neurology and Psychiatry, Gifu University School of Medicine, Gifu, Japan; M.H. Lader, Institute of Psychiatry, University of London, London, England; I .A. Lieberman, Hillside Hospital, Long Island Jewish Medical Center, Glen Oaks, New York, USA; L. Lindstrom, Psychiatric Research Center, University of Uppsala, Uppsala, Sweden; D.K. Luscombe, Welsh School of Pharmacy, University of Wales Institute of Science and Technology, Cardiff, Wales; H. Y. Meltzer, Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; R.R. Owen, National Institute of Mental Health, Bethesda, Maryland, USA; I.G. Small, Department of Psychiatry, Larue D. Carter Memorial Hospital, Indiana University School of Medicine, Indianapolis, Indiana, USA; P. Turner, Department of Clinical Pharmacology, St Bartholomew's Hospital Medical College, University of London, London, England; I .A. Vale, West Midlands Poisons Unit, Dudley Road Hospital, Birmingham, England.
Contents
Summary .. ....................... ... .. ....... ......... ......... ................... ... ............ ............. .... ...... ....... ............. 723 I. Overview of Pharmacodynamic Properties ....................................... .. ................................ 725 1.I Effects on Central Neurotransmitter Systems .. ............ .................... .. ........... ............... 727 1.2 Differential Effects on Central Dopaminergic Systems ............................ ..... .............. 728 1.3 Behavioural Effects in Animals ......... ................. .................. ................ ................... ...... 729 1.4 Neuroendocrinological Effects ....... .. .......................... ..... ......................... ............... ....... 729 2. Pharmacokinetic Properties ... ...... .. ........... ..... ........ .. ....... .. ..... ........ .. ...... .. ........ ..................... 730 2.1 Absorption and Plasma Concentrations ...................... ........ ............................. ........ .... 730 2.2 Distribution ......... ..................... .. ....... .. .... .......... ............ ..... .......... .......... ......................... 731 2.3 Metabolism and Excretion .. ............................ ........... ........ .................. .......... ................ 731 3. Therapeutic Use in Schizophrenia ..................... ........................................... ....................... 732 3.1 Noncomparative Studies ........... ....... .. ............................... .. ........................ ........ ........... 732 3.2 Comparisons with Placebo .. ... .... .. ..... .... .............. ... .. ......... ..... ...... .. ....................... .. ....... 732 3.3 Comparisons with Other Antipsychotics ..................................................... ...... ........... 733 3.3.1 Chlorpromazine ........ ........................... ................... ............... .. ... ............................ 733 3.3.2 Haloperidol ... ... ........... .. .. .............. .... ... .. ..... ....... .......... ............ ..................... ....... ... 735 3.4 Use in Treatment-Resistant Schizophrenia .......................... ........................................ 735 3.4.1 Noncomparative Studies ................................................ ........ ............................... 735 3.4.2 Comparisons with Other Antipsychotics .......................... .......... .............. ....... .... 736
723
Clozapine: A Review
4. Adverse Effects ............................................................................................. ......................... 4.1 Haematological Effects .................................................. ................................................. 4.2 Extrapyramidal Effects ............ ..................................................... :................................. 4.3 Other Effects .................................................................................................................... 5. Dosage and Administration .................................................................................................. 6. Place of Clozapine in Therapy .................................................... .........................................
739 739 740 740 741 742
Summary Synopsis
C/ozapine. an antipsychotic agent of the dibenzodiazepine class. is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable. or on some criteria superior. therapeutic efficacy to perphenazine. levomepromazine. haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover. clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential. the relatively high incidence of clozapine-induced agranulocytosis (I to 2% of patients) is a major factor restricting the drug's wider use in psychiatric practice. In accordance with current guidelines. clozapine therapy. performed in conjunction with close haematological monitoring. is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy. and in those unable to tolerate such therapy. In such appropriately selected patients. clozapine represents an important alternative to the classic antipsychotics.
Pharmacodynamic Properties
In comparison with the classic anti psychotics, clozapine is a relatively weak antagonist at striatal dopamine D2-receptors, and produces a more potent blockade of central dopamine DI-, cholinergic, serotonergic S2-, histamine HI-, and 0'1- and a2-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine D 1- and D2-receptors; at clinically effective doses central dopamine D2-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine DI-receptor function and produces down-regulation of serotonergic S2-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentiallyon mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine's marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic anti psychotics, clozapine has minimal effects on plasma prolactin levels in humans.
Pharmacokinetic Properties
Peak plasma concentrations of clozapine are reached at I to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 ILg/L (corresponding to daily doses of'" 0.5 to 12.0 mg/kg). Maximum
724
Drugs 40 (5) 1990
and minimum plasma c10zapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma c10zapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, c10zapine undergoes extensive metabolism via N-oxidation, N-demethylation and dehalogenation, with unchanged c10zapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route ('" 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use
Noncomparative studies in hospitalised patients with schizophrenia have indicated that c10zapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to c10zapine is characterised by an initial sedative/anxiolytic effect which is followed after I to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term c10zapine maintenance therapy (~ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of c10zapine (~ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic anti psychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (~ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, c10zapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the 'psychomotor plus' symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, c10zapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of c10zapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that c10zapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic anti psychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (~ 2.5 years). The aetiological/c1inical factors predictive of therapeutic benefit with c10zapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of c10zapine (~ 900 mg/day) versus that of chlorpromazine (~ 1800 mg/day) in terms of physicians' and ward nurses' ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement.
Adverse Effects
Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of c1ozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (1\ %), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to c10zapine and necessitating its withdrawal (predominantly toxic delirium and sedation) oc-
725
Clozapine: A Review
curred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in I to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional anti psychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration
Clozapine may be administered orally or intramuscularly. The manufacturer recommends initiation of clozapine therapy with 25 to 75 mgjday administered in 2 or 3 divided doses, followed by titration in 25 to 50 mgjday increments to achieve a target dose of 300 to 450 mg/day after 2 weeks. Subsequent dosage increases of ~ 100 mgjday should be performed no more than twice weekly, to a maximum dose of 900 mg/day. After initial titration, the dose should be progressively reduced to the minimum level necessary to maintain clinical remission. In view of the continuing risk of agranulocytosis, weekly haematological surveillance is essential during the initial 18 weeks of clozapine administration; thereafter monthly monitoring is considered satisfactory. Clozapine is contraindicated in conjunction with drugs with the potential to depress bone marrow function/induce agranulocytosis, as well as in patients with severe CNS depression, myeloproliferative disorders or a history of drug-induced agranulocytosis.
Clozapine [8-chloro-ll-( 4-methyl-l-piperazinyl)-5H-dibenzo [1,4] diazepine] is a dibenzodiazepine derivative (fig. 1) with a pharmacological and therapeutic profile that distinguishes it from the classic anti psychotics (phenothiazines, butyrophenones, diphenylbutylpiperidines and thioxanthenes). In contrast to these latter groups, c10zapine exerts a relativel~ weak antidopaminergic action within the CNS and is only marginally effective in several animal behavioural tests considered to be specific for drugs with antipsychotic properties. Clinically, c10zapine is regarded as an atypical antipsychotic on account of its low propensity to produce extrapyramidal side effects and its lack of stimulatory effect on prolactin secretion. The drug has been used in the treatment of acute and chronic schizophrenia, mania, hypomania and other acute psychoses of diverse aetiology, as well as behavioural disorders characterised by aggressiveness, impulsiveness and excitability. This review focuses on the use of c10zapine in the treatment of schizophrenic disorders, defined for this purpose as schizophrenia, schizophreni-
form disorder and schizoaffective disorder (code 295 in the revised DSM-I1I classification).
1. Overview of Pharmacodynamic Properties It is generally acknowledged that the therapeutic effects of antipsychotic drugs are related to their actions on central dopaminergic mechanisms (Carlsson 1978; Creese et al. 1976; Seeman et al. 1976). The clinical potency of typical and atypical anti psychotics is closely correlated with their in vitro affinity for central dopamine D2-receptors (Peroutka & Snyder 1980; Richelson 1984), while therapeutic doses of these compounds produce a substantial in vivo blockade of central dopamine D2-receptors in patients with schizophrenia (Farde et al. 1988). In the case of c1ozapine, it appears unlikely that dopamine D2-receptor antagonism can fully account for the drug's antipsychotic efficacy. Although an effective antipsychotic, c10zapine differs from the typical antipsychotics in producing rela-
726
Drugs 40 (5) 1990
Clozapine
Fig. 1. C10zapine metabolites identified in the urine of schizophrenic and manic patients following oral administration of 300 to 800 mgjday (adapted from Stock et al. 1977).
tively weak antagonism at central dopamine 02receptors, more pronounced inhibition of dopamine 0 I-mediated activation of adenylate cyclase, and potent blockade of central serotonergic, adrenergic and cholinergic receptors (Altar et al. 1986; Souto et al. 1979). Moreover, c10zapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy and suppression of dopamine-induced stereotypy) considered to be predictive of antipsychotic activity. It has been suggested that the antipsychotic efficacy of c1ozapine might be related to central dopamine 01- or a combination of dopamine 01- and D2-receptor antagonism (Altar et al. 1988; Andersen & Braes-
trup 1986; Coward et al. 1989; Criswell et al. 1989), with serotonergic S2-receptor antagonism possibly playing a supplementary role (Meltzer 1989). The therapeutic effects of antipsychotic drugs are presumed to be mediated by mesolimbic and mesocortical dopaminergic pathways (Delini-Stula 1986; Stevens & Livermore 1978), while the neostriatum has been implicated in the extrapyramidal side effects associated with these drugs (Davis & Casper 1977; Hornykiewicz 1977). In view of the low incidence of extrapyramidal side effects with c1ozapine, it has been suggested that the atypical pharmacological profile of this drug might be attributable to a selective action on mesolimbic
Clozapine: A Review
727
dopaminergic mechanisms (Borison & Diamond 1983). 1.1 Effects on Central Neurotransmitter Systems In contrast to the classic anti psychotics, c1ozapine displays low in vitro affinity for striatal dopamine D2-receptors, and relatively greater affinity for striatal dopamine DI-, cortical/subcortical serotonin S2- and S3- and central al- and a2-adrenergic, histamine HI- and muscarinic receptors (Altar et al. 1986; Andersen & Braestrup 1986; Biirki 1986; Biirki et al. 1975b; Coward et al. 1989; Eichenberger 1984; Riehelson 1984; Watling et al. 1990; Wilmot & Szczepanik 1989) [tables I & II). In vitro binding is not necessarily predictive, however, of the functional effects of drug-receptor interactions in the intact organism. Clozapine exhibits relatively potent serotonergic S2- (Fink et al. 1984; Leysen et al. 1978), serotonergic S3- (Ashby et al. 1989; Watling et al. 1990), ai-adrenergic (Bartholini et al. 1973; Blumberg et al. 1976), histamine H 1- (Niemegeers & Janssen 1979) and muscarinic (Miller & Hiley 1976) antagonist activity (fig. 2), and appears to induce preferential blockade of dopamine DI- (versus dopamine 02-) receptors in vivo (Coward et al. 1989). In contrast to the classic anti psychotics, c10zapine shows greater potency in binding to the dopamine DI-receptor in vivo and inhibiting dopamine-stimulated adenylate cyclase activity than in competing for [3H]SCH 23390 (a
selective dopamine D I-antagonist) binding in vitro (Andersen & Braestrup 1986; Andersen et al. 1986). Positron emission tomography scan studies of relative dopamine DI- and D2-receptor occupancy in patients with schizophrenia undergoing antipsychotic therapy have indicated that, at clinically effective doses (300 to 600 mg/day), c10zapine produces comparable degrees of dopamine DI- and D2receptor blockade, and less dopamine D2-receptor blockade than do the classic anti psychotics (Farde et al. 1988, 1989), thereby lending support to the hypothesis that dopamine DI-antagonism may be of relevance to c1ozapine's antipsychotic action. Long term administration of c10zapine enhances striatal dopamine D 1- (but not dopamine D2-) receptor function in rats (Clark & White 1987; Jenner et al. 1985; Rupniak et al. 1985), and results in down-regulation of cortical serotonin S2-receptors (Lee & Tang 1984; Reynolds et al. 1983; Wilmot & Szczepanik 1989), further suggesting that an interaction with these 2 neurotransmitter systems may be a significant component of the drug's antipsychotic action. Pronounced serotonin S2- in relation to dopamine D2-receptor blockade has been postulated to be the central factor distinguishing atypical from typical anti psychotics (Meltzer et al. I 989c). It is noteworthy that serotonin S2-antagonist activity in antipsychotic drugs has been previously associated with efficacy against the negative symptoms of schizophrenia and a low propensity to induce extrapyramidal symptoms (Ceulemans et al. 1985).
Table I. Effects of clozapine . chlorpromazine and haloperidol on radioligand binding to preparations of human caudate nucleus and frontal cortex in vitro (after Richelson 1984) Radioligand
Receptor
Receptor affinity Ki (nmol/L) clozapine
[3Hlspiperone
Dopamine 02
chlorpromazine
haloperidol
180
19
4
12
[3Hlquinuclidinyl benzilate
Muscarinic
70
24000
[3Hldoxepin
Histamine HI
2.8
9
1900
[3Hlprazosin
Adrenergic al
9
2.6
[3Hlrauwolscine (a-yohimbine)
Adrenergic a 2
160
750
6.1 3800
728
Drugs 40 (5) 1990
Table II. Ellects of clozapine , chlorpromazine and haloperidol on dopamine 0,- and D2-receptor binding to rat striatum in vitro and on dopamine D,-receptor binding to mouse brain in vivo (after Andersen et al. 1986) Compound
Clozapine Chlorpromazine Haloperidol
Inhibition of [3HlSCH 23390 binding in vivo (EDso; mg/kg)'
Dopamine receptor allinity in vitro (Kj; nmol/L)b 0,
02
10.2
55
90
7.3
25
4.6
72.5
76
2.6
a The EDso value is the antipsychotic dose which reduces the specific in vivo binding of [3HlSCH 23390 by 50% in mouse brain. b Data from Andersen et al. (1985).
1.2 Differential Effects on Central Dopaminergic Systems Biochemical and neurophysiological studies in animals indicate that c10zapine may act preferentially on mesolimbic rather than neostriatal dopaminergic neurons. Clozapine has been reported to be more effective in increasing dopamine turnover and release in the nucleus accumbens or olfactory tubercle than in the neostriatum (Anden & Stock 1973; Bartholini 1976; Bowers & Rozitis 1974; Stawarz et al. 1975; Westerink & Korf 1976; Westerink et al. 1977; Zivkovic et al. 1975), although other studies have failed to confirm this selective action (Bartholini et al. 1975; Bowers & Rozitis 1976; Imperato & Angelucci 1988; Westerink & Korf 1975; Wilk & Glick 1976). On acute administration, c10zapine selectively enhanced neuronal activity in the mesolimbic system (Hand et al. 1987; White & Wang 1983) and increased dopamine release in the nucleus accumbens but not in the neostriatum (Huff & Adams 1980; Lane & Blaha 1986). In contrast, on chronic administration c10zapine selectively depressed neuronal activity in the mesolimbic system (Chiodo & Bunney 1983; White & Wang 1983) and reduced dopamine release in the nucleus accumbens (Blaha & Lane 1987; Lane et al. 1988). Dopamine synthesis and metabolism, however, were
nonselectively increased in both the neostriatum and mesolimbic system during short term c1ozapine administration (Walters & Roth 1976; Wilk et al. 1975). A possible explanation for the apparently selective action of c10zapine on the mesolimbic system might be a concomitant interaction with other neurotransmitter systems compensating for dopaminergic blockade in the neostriatum. Antagonism at cholinergic and/or ai-adrenergic receptors has been suggested to account for the apparently selective action of c10zapine on mesolimbic dopaminergic neurons, and the consequent low incidence of extrapyramidal side effects (see section 4.2) [Chiodo & Bunney 1983; Lane et al. 1988; Miller & Hiley 1974; Snyder et al. 1974]. The amygdala, which receives dopaminergic input from the substantia nigra and ventral tegmentum, may be an additional site of action of c10zapine. Amygdaloid neurons are excited by short (Rebec et al. 1981 , 1983) and long term (Anderson & Rebec 1986; Rebec & Anderson 1986) c10zapine administration, but are generally unresponsive to haloperidol and other standard anti psychotics. This differential effect is not observed in other forebrain
1---1"'100 I"'r--1"' 10 100 10
0.1
.2 ~
8'
...J
0.1 H
S
M
0.01
NA
0,01 Haloperido!
ClozaChlorpromazine pine
Fig. 2. Pharmacological profiles of action ofclozapine. chlorpromazine and haloperidol in relation to their antidopaminergic effects. The in vivo antagonistic potencies of each compound at adrenergic (NA), serotonergic (S). muscarinic (M) and histamine (H) receptors are expressed relative to its antagonistic potency at dopaminergic (DA) receptors (arbitrarily chosen as unity) [adapted from Delini-Stula 1986).
729
Clozapine: A Review
sites that receive dopaminergic input, including the neostriatum and nucleus accumbens, where clozapine and haloperidol display comparable effects on neuronal activity (Rebec et al. 1979, 1980). 1.3 Behavioural Effects in Animals Results from a series of animal behaviour models routinely used to screen for antipsychotic activity suggest that the neostriatum is relatively unresponsive to clozapine. In rodents, clozapine induces little or no catalepsy (Bartholini et al. 1972; Biirki et al. 1975a; De Maio 1972; Honma & Fukushima 1978), catalepsy being a characteristic response to neostriatal dopamine receptor blockade (Carlsson 1978). Amphetamine-induced locomotion, which is apparently mediated by enhanced dopaminergic neurotransmission in the nucleus accumbens (Kelly & Iversen 1976; Pijnenburg et al. 1976), is inhibited by acute administration of clozapine, whereas amphetamine-induced stereotypy (gnawing, grooming and sniffing), a response dependent on the integrity of the dopaminergic input to the neostriatum (Groves & Rebec 1976), is unaffected by the drug (Iversen & Koob 1977). Similarly, clozapine inhibits apomorphine-induced locomotion, but does not interfere with apomorphineinduced stereotypy (Ljungberg & Ungerstedt 1978). Hyperactivity elicited by direct injection of dopamine into the mesolimbic nuclei is blocked by clozapine at doses an order of magnitude lower than those required to block behaviours elicited by direct striatal dopamine injections (Costall & Naylor 1976). Chronic clozapine administration supersensitises those behaviours mediated via mesolimbic dopaminergic pathways (i.e. dopamine-induced locomotion), but not those mediated via neostriatal systems (i.e. dopamine-induced stereotypy) [Halperin et al. 1989). Drug-induced suppression of conditioned avoidance behaviour, which is considered predictive of antipsychotic activity (Kuribara & Tadokoro 1981; Niemegeers et al. 1969), has been demonstrated during acute clozapine administration in the rat (Biirki et al. 1975a; Davidson & Weidley 1976; Iorio et al. 1983; Sanger 1985). However, the
suppression of avoidance responding was manifest with relatively high (sedative) doses of clozapine and, in contrast to haloperidol, was associated with the rapid development of tolerance on repeat administration (Sanger 1985), thereby suggesting that this effect of clozapine is not specifically related to its antipsychotic action. In its effects on schedule-controlled behaviours (those reinforced by food or electrical self-stimulation), clozapine more closely resembled anxiolytics such as benzodiazepines than the classic anti psychotics (Atrens et al. 1976; Canon & Lippa 1977; Spealman et al. 1983; Wenger 1979). As an antipsychotic, clozapine is atypical in producing no oral dyskinesia in the rat on long term administration (Johansson et al. 1986; See & Ellison 1990). Moreover, in contrast to haloperidol, clozapine fails to elicit an acute dyskinetic syndrome in monkeys primed by long term haloperidol or fluphenazine pretreatment (Gunne & Barany 1979; Kovacic et al. 1986; Liebman & Neale 1980) or to modify tardive dyskinesia-like symptoms arising after antipsychotic withdrawal (Gunne & Barany 1979; Kovacic et al. 1986). 1.4 Neuroendocrinological Effects In the rat, acute administration of clozapine was associated with a transient rise in serum prolactin, corticotrophin (adrenocorticotrophic hormone) and corticosterone levels (Biirki et al. 1975a; Gudelsky et al. 1987b; Iorio et al. 1983) and an increase in the activity of tuberoinfundibular dopaminergic neurons (Gudelsky et al. 1987a), which have previously been shown to exert an inhibitory influence on prolactin release from the pituitary (Gudelsky 1981). In contrast to the prolonged stimulation of prolactin secretion produced by classic antipsychotics (Meltzer & Fang 1976), clozapine has minimal effects on serum prolactin levels in humans, despite its ability to block pituitary dopamine receptors (Kane et al. 1981; Meltzer 1989; Meltzer et al. 1979). It has been suggested that the failure of clozapine to stimulate prolactin secretion in humans may be the result of a clozapine-induced increase in tuberoinfundibular dopamine re-
730
Drugs 40 (5) 1990
-
(')
c:i
~
.~
"S
o
U
~ 3o
'"
If)
.r::
:2
HP
BPRS, CGI
NS
ClZ == PPZ
ClZ> lMP
ClZ == HP
BPRS
AMP
ClZ > HP BPRS; SGE
ClZ "CPZ
ClZ;;' CPZ
BPRS
ClZ 200-300 CPZ 200-600
6
ClZ == CPZ ClZ == CPZ
BPRS; GCS
6
ClZ 50-300 CPZ 75-600
ClZ " PPZ
ClZ < HP
ClZ " HP
ClZ == CPZ
ClZ > CPZ
BPRS
6
ClZ " CPZ
ClZ "CPZ
ClZ> CPZ
BPRS; SGE
ClZ 200-100(Jd CPZ 75-800d
7
CLZ 75-450 CPZ 150-900
ClZ == CPZ
ClZ== CPZ
ClZ;;' CPZ
extrapyramidal symptoms
6
6
ClZ 160-340 CPZ 130-410
Results overall efficacyb
BPRS; NOSIE
Rating scale
CLZ 600C CPZ 600C
6
Duration of treatment (weeks)
ClZ 150-300 CPZ 150-300
Daily dose (mg)
a Number of patients evaluated on completion of the study. b Overall therapeutic efficacy is assessed in terms of drug effect on individual and grouped parameters of psychiatric and social function. c Mean dose. d Mean clozapine and chlorpromazine doses 277 and 283 mg/day, respectively. Abbreviations and symbols: r = randomised; sb = single-blind; db = double-blind; co = crossover; p= parallel group trial; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression Scale; NOSIE = Nurses' Observation Scale for Inpatient Evaluation; GCS = Global Clinical Scale; SGE = Subjective Global Evaluation; AMP = Arbeitsgemeinschaft fUr Methodik und Dokumentation in der Psychiatrie; NS = not stated; == = similar effect; " tendency towards greater effect; > = statistically significant greater effect (p < 0.05); " = tendency towards a lower effect; < = statistically significant lower effect (p < 0.05).
Perphenazine (PPZ) Rodova et al. (1973)
12 17
12 12
SchOneil & Klieser (1988)
levomepromazine (lMP) Angst et al. (1971)
47 41
Itoh et al. (1977)
20
16 19
Guirguis et al. (1977)
Haloperidol (HP) Gerlach et al. (1974)
20 21
22 14
No. of patients·
Ekblom & Haggstrom (1974)
Chlorpromazine (CPZ) Chiu et al. (1976)
Reference
Table IV. Some single· and double-blind comparative studies of clozapine (ClZ) and other anti psychotics in the treatment of patients with schizophrenia
......
:s......
-I>..
oa
...,\:) ::::
.j:>.
Clozapine: A Review
clozapine than with chlorpromazine, commenced later, and were of shorter duration (Guirguis et al. 1977).
3.3.2 Haloperidol Short term (6 to 12 weeks) trials in patients with schizophrenia have indicated that clozapine 75 to 800 mg/day has either equivalent (Itoh et al. 1977) or significantly superior (Gerlach et al. 1974; SchOnell & Klieser 1988) overall therapeutic efficacy to haloperidol 3 to 40 mg/day. However, the two drugs differ markedly in their spectra of antipsychotic effects. While clozapine produced significant improvements in anxiety, tension, and the productive and negative schizophrenic symptoms, haloperidol was effective against the core symptoms of schizophrenia but lacked significant action against anxiety and tension (Gerlach et al. 1974). Clozapine proved to be significantly superior to haloperidol in its antidelusional, contact-promoting and anxiolytic/sedative effects (BPRS items: somatic concern, anxiety, guilt feelings, conceptual disorganisation, tension, mannerisms/posturing and hostility) [Gerlach et al. 1974; Itoh et al. 1977]. Although haloperidol was reported to be significantly superior to clozapine in improving motor retardation and blunted affect in the general schizophrenic population (ltoh et al. 1977), the converse was true in patients with predominantly negative schizophrenic symptoms, with clozapine producing a significantly greater improvement in emotional withdrawal, motor retardation and blunted affect than haloperidol (Paunovic et al. 1988). The therapeutic superiority of clozapine over haloperidol was particularly pronounced in severely disturbed patients with added symptoms of anxiety, tension and psychomotor agitation (Gerlach et al. 1974). The incidence of extrapyramidal side effects (notably hyperkinesia and akathisia) was significantly higher with haloperidol, while clozapine produced more marked hypersalivation (Itoh et al. 1977).
735
3.4 Use in Treatment-Resistant Schizophrenia A subgroup of patients with schizophrenia, constituting up to 20% of the total, is refractory to treatment with the classic antipsychotics and has a poor long term prognosis (Davis et al. 1980). Additionally, of the patients who initially respond to classic antipsychotic therapy, approximately 20 to 30% are liable to relapse despite maintenance therapy (Kane & Lieberman 1987). To this subgroup of drug-refractory patients must be added those who fail to tolerate the classic anti psychotics at clinically effective doses because of the development of severe extrapyramidal side effects, and the estimated 15% of patients who develop tardive dyskinesia on long term therapy (Jeste & Wyatt 1981; Klawans et al. 1980). In this section, clinical experience with clozapine is described in these various patient subgroups which collectively constitute a distinct category of 'treatment-resistant schizophrenia' .
3.4.1 Noncomparative Studies Several retrospective and prospective noncomparative studies have demonstrated that a substantial proportion of patients with chronic treatmentresistant schizophrenia show significant clinical improvement during clozapine therapy. Despite methodological limitations, results from short and long term (1 month to 13 years) retrospective studies consistently indicate that approximately 30 to 50% of patients with treatment-resistant schizophrenia show a markedly better improvement on clozapine than on previous standard antipsychotic therapy (Kuha & Miettinen 1986; Leppig et al. 1989; Lindstrom 1988; Naber et al. 1989; Povlsen et al. 1985). In these patients, positive schizophrenic symptoms, particularly hallucinations, delusions, unusual thought content, psychomotor hyperactivity and aggression, appeared to be most markedly reduced by clozapine (Kuha & Miettinen 1986; Leppig et al. 1989; Naber et al. 1989), although negative schizophrenic symptoms of mutism, blunted affect and anergia were also favourably influenced, most notably in the subgroups with hebephrenia and chronic residual schizophrenia
736
(Naber et al. 1989). Clozapine also had a beneficial effect on the level of social adaptation in patients with chronic treatment-resistant schizophrenia: of 62 in this category who were maintained on clozapine for 2 years, 39% were in employment during this period compared with only 3% in the year preceding initiation of clozapine therapy (Lindstrom 1988). Characteristically, clozapine produced a pronounced alleviation of positive schizophrenic symptoms and an improvement in the quality of remission during the initial 6 months of therapy, while its effects on negative schizophrenic symptoms became increasingly evident with continued therapy. Over the following 6-month to 3.5-year treatment period, positive and negative symptoms improved steadily and significantly, while the improvement in work capacity attained significance after 2.5 years. Consolidation of the improvement in the quality of remission during this period was attributable to the parallel improvements in negative symptoms and work capacity and a reduction in the frequency of relapses (Panteleeva et al. 1978). Prospective studies of the clinical efficacy of clozapine in chronic treatment-resistant schizophrenia have demonstrated significant improvements (> 20% decrease in total BPRS score from baseline) in approximately 40 to 60% of patients when assessed after 1.5 to 6 months' therapy; these were subsequently maintained during long term (~ 4 years) follow-up treatment (Mattes 1989; Meltzer et al. 1989a,b; Owen et al. 1989; Small et al. 1987). Moreover, the improvement in psychopathology resulting from clozapine therapy was associated with an improvement in social function, as assessed in terms of the Quality of Life and Global Assessment ratings, in the outpatient setting (Meltzer et al. 1989a,b) and a marked reduction in the need for rehospitalisation (Meltzer et al. 1989a). Analysis of the responses of the various patient subgroups constituting treatment-resistant schizophrenia indicated that patients intolerant of classic antipsychotics and showing tardive dyskinesia/extrapyramidal side effects responded significantly
Drugs 40 (5) 1990
better to clozapine therapy (~ 3 months duration), as assessed by total BPRS rating, than those refractory to previous antipsychotic therapy, while the outcome in patients with a history of antipsychotic-induced akathisia was marginally superior to that in those without a history ofakathisia (Owen et al. 1989). The same study demonstrated a marked symptomatic improvement after 3 or more months of clozapine therapy in 5 of 11 patients (45%) with moderate-to-severe tardive dyskinesia induced by previous antipsychotic therapy. In accordance with the results of retrospective studies, the greatest improvement in psychopathology (total BPRS score) occurred during the initial 6 weeks of clozapine therapy, although only 45% of drug responders were identified during this period (Meltzer et al. 1989b); after 3 and 12 months' therapy 74% and 100%, respectively, of drug responders were identified (Meltzer et al. 1989b). This would suggest that a 6- to 12-month treatment period may be appropriate before deciding to discontinue clozapine because of insufficient response. While clinical responsiveness to clozapine in treatment-resistant schizophrenia is reportedly unrelated to factors of age, sex, duration of illness, hospitalisation and presence or history of tardive dyskinesia (Owen et al. 1989), the influence of disease severity is unclear. A favourable clinical response to prolonged (~ 6 weeks) clozapine therapy has variously been associated with less severe underlying psychopathology, as rated by BPRS and Composite Schizophrenia Syndrome scores (Small et al. 1987) and with more severe psychopathology, as rated by total BPRS scores and BPRS factor scores for Paranoid Disturbance and Thinking Disturbance (Meltzer et al. 1989b). 3.4.2 Comparisons with Other Antipsychotics
Several recent short term (6 to 8 weeks) doubleblind studies have confirmed the antipsychotic efficacy of clozapine and have provided evidence of its superiority over chlorpromazine in well-defined groups of patients with treatment-resistant schizophrenia (Borison et al. 1988; Claghorn et al. 1987; Conley et al. 1988; Herrera et al. 1988; Kane et al. 1988) [table V]. A noteworthy feature of these stud-
TD or EPS induced on prior antipsychotic therapy
63 c 61 c
12 12
8 8
126c 139c
Claghorn et al. (1987)
Conley et al. (1988)
Herrera et al. (1988)
Kane et al. (1988)d
CLZ "" 900 CPZ"" 1800
Daily dose (mg)
CLZ 900 CPZ 1800
CLZ "" 900 CPZ "" 1800 + BTM "" 6
r,p,mc,pb CLZ "" 900 CPZ"" 1800 +BTM",,6
p,pb
r,p,pb
r,p,mc,pb CLZ 150-900 CPZ 300-1800
r,p,pb
Study design
6
6
6
8
6
BPRS; CGI; NOSIE; AIMS; SANRS
BPRS; AIMS; SANRS
BPRS; CGI; NOSIE; AIMS; SANRS
BPRS; CGI; NOSIE; AIMS; SANRS
BPRS
Duration Rating of scale treatment (weeks)
CLZ > CPZ
CLZ ,. CPZ
CLZ > CPZ
CLZ > CPZ
CLZ> CPZ
overall efficacyb
Results
CLZ
== CPZ CPZ> CLZ
NS
CLZ
CPZ ,. CLZ
CLZ
NS
== CPZ
== CPZ
tardive dyskinesia
CPZ,. CLZ
extrapyramidal symptoms
==
a Number of patients evaluated on completion of the study, unless otherwise stated, b Overall therapeutic efficacy is assessed in terms of drug effect on individual and grouped parameters of psychiatric and social function. c Number of patients included in the endpoint analysis on completion of a minimum of 1 week's therapy, d Multicentre study incorporating those patients referred to in the single centre studies of Borison et ai., Conley et al. and Herrera et al. Abbreviations and symbols: BTM = benztropine mesylate; HP = haloperidol; TD = tardive dyskinesia; EPS = extrapyramidal symptoms; NS = not stated; r = randomised; p = parallel group trial; mc = multicentre trial; pb = placebo washout period; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression Scale; NOSIE = Nurses' Observation Scale for Inpatient evaluation; SANRS = Simpson-Angus Neurological Rating scale; AIMS = Abnormal Involuntary Movement Scale; = similar effect; ,. tendency towards greater effect; > = statistically significant greater effect (p < 0.05); "" = tendency towards a lower effect; < = statistically significant lower effect (p < 0.05),
Refractory to previous antipsychotic therapy; proven refractoriness to HP (60 mg/day)
Proven refractoriness to HP (60 mg/day)
Refractory to previous antipsychotic therapy; proven refractoriness to HP (60 mg/day; CGI ,. 4; BPRS ,. 36)
Refractory to previous antipsychotic therapy; proven refractoriness to HP (,. 60 mg/day)
14 13
No. of Therapeutic status patients a
Borison et al. (1988)
Reference
Table V. Some double-blind comparative studies of clozapine (CLZ) and chlorpromazine (CPZ) in patients with treatment-resistant schizophrenia
---I
---I
,.:
(ii'
Drugs 40 (5): 722-747, 1990 00 12-6667/90/00 11-0722/$13.00/0 © Adis International Limited All rights reserved. DREND2143
Clozapine
A Review of its Pharmacological Properties, and Therapeutic Use in Schizophrenia
Andrew Fitton and Rennie C. Heel Adis Drug Information Services, Auckland, New Zealand
Various sections of the manuscript reviewed by: M . Ackenheil, Psychiatric Hospital, University of Munich, Munich, Federal Republic of Germany; D.E. Casey, Psychiatric Service, Veterans Administration Medical Center, Portland, Oregon, USA; W. W. Fleischhacker, Department of Psychiatry, Innsbruck University Clinics, Innsbruck, Austria; I. Gerlach, St Hans Hospital, Roskilde, Denmark; G.A. Gudelsky, Department of Psychiatry, University Hospitals of Cleveland, Cleveland, Ohio, USA; H. Kaiya, Department of Neurology and Psychiatry, Gifu University School of Medicine, Gifu, Japan; M.H. Lader, Institute of Psychiatry, University of London, London, England; I .A. Lieberman, Hillside Hospital, Long Island Jewish Medical Center, Glen Oaks, New York, USA; L. Lindstrom, Psychiatric Research Center, University of Uppsala, Uppsala, Sweden; D.K. Luscombe, Welsh School of Pharmacy, University of Wales Institute of Science and Technology, Cardiff, Wales; H. Y. Meltzer, Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; R.R. Owen, National Institute of Mental Health, Bethesda, Maryland, USA; I.G. Small, Department of Psychiatry, Larue D. Carter Memorial Hospital, Indiana University School of Medicine, Indianapolis, Indiana, USA; P. Turner, Department of Clinical Pharmacology, St Bartholomew's Hospital Medical College, University of London, London, England; I .A. Vale, West Midlands Poisons Unit, Dudley Road Hospital, Birmingham, England.
Contents
Summary .. ....................... ... .. ....... ......... ......... ................... ... ............ ............. .... ...... ....... ............. 723 I. Overview of Pharmacodynamic Properties ....................................... .. ................................ 725 1.I Effects on Central Neurotransmitter Systems .. ............ .................... .. ........... ............... 727 1.2 Differential Effects on Central Dopaminergic Systems ............................ ..... .............. 728 1.3 Behavioural Effects in Animals ......... ................. .................. ................ ................... ...... 729 1.4 Neuroendocrinological Effects ....... .. .......................... ..... ......................... ............... ....... 729 2. Pharmacokinetic Properties ... ...... .. ........... ..... ........ .. ....... .. ..... ........ .. ...... .. ........ ..................... 730 2.1 Absorption and Plasma Concentrations ...................... ........ ............................. ........ .... 730 2.2 Distribution ......... ..................... .. ....... .. .... .......... ............ ..... .......... .......... ......................... 731 2.3 Metabolism and Excretion .. ............................ ........... ........ .................. .......... ................ 731 3. Therapeutic Use in Schizophrenia ..................... ........................................... ....................... 732 3.1 Noncomparative Studies ........... ....... .. ............................... .. ........................ ........ ........... 732 3.2 Comparisons with Placebo .. ... .... .. ..... .... .............. ... .. ......... ..... ...... .. ....................... .. ....... 732 3.3 Comparisons with Other Antipsychotics ..................................................... ...... ........... 733 3.3.1 Chlorpromazine ........ ........................... ................... ............... .. ... ............................ 733 3.3.2 Haloperidol ... ... ........... .. .. .............. .... ... .. ..... ....... .......... ............ ..................... ....... ... 735 3.4 Use in Treatment-Resistant Schizophrenia .......................... ........................................ 735 3.4.1 Noncomparative Studies ................................................ ........ ............................... 735 3.4.2 Comparisons with Other Antipsychotics .......................... .......... .............. ....... .... 736
723
Clozapine: A Review
4. Adverse Effects ............................................................................................. ......................... 4.1 Haematological Effects .................................................. ................................................. 4.2 Extrapyramidal Effects ............ ..................................................... :................................. 4.3 Other Effects .................................................................................................................... 5. Dosage and Administration .................................................................................................. 6. Place of Clozapine in Therapy .................................................... .........................................
739 739 740 740 741 742
Summary Synopsis
C/ozapine. an antipsychotic agent of the dibenzodiazepine class. is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable. or on some criteria superior. therapeutic efficacy to perphenazine. levomepromazine. haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover. clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential. the relatively high incidence of clozapine-induced agranulocytosis (I to 2% of patients) is a major factor restricting the drug's wider use in psychiatric practice. In accordance with current guidelines. clozapine therapy. performed in conjunction with close haematological monitoring. is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy. and in those unable to tolerate such therapy. In such appropriately selected patients. clozapine represents an important alternative to the classic antipsychotics.
Pharmacodynamic Properties
In comparison with the classic anti psychotics, clozapine is a relatively weak antagonist at striatal dopamine D2-receptors, and produces a more potent blockade of central dopamine DI-, cholinergic, serotonergic S2-, histamine HI-, and 0'1- and a2-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine D 1- and D2-receptors; at clinically effective doses central dopamine D2-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine DI-receptor function and produces down-regulation of serotonergic S2-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentiallyon mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine's marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic anti psychotics, clozapine has minimal effects on plasma prolactin levels in humans.
Pharmacokinetic Properties
Peak plasma concentrations of clozapine are reached at I to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 ILg/L (corresponding to daily doses of'" 0.5 to 12.0 mg/kg). Maximum
724
Drugs 40 (5) 1990
and minimum plasma c10zapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma c10zapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, c10zapine undergoes extensive metabolism via N-oxidation, N-demethylation and dehalogenation, with unchanged c10zapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route ('" 50% of administered dose) and the faecal route (35% of administered dose). Therapeutic Use
Noncomparative studies in hospitalised patients with schizophrenia have indicated that c10zapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to c10zapine is characterised by an initial sedative/anxiolytic effect which is followed after I to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term c10zapine maintenance therapy (~ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia. Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of c10zapine (~ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic anti psychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (~ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, c10zapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the 'psychomotor plus' symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, c10zapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of c10zapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms. Retrospective and prospective noncomparative studies have indicated that c10zapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic anti psychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (~ 2.5 years). The aetiological/c1inical factors predictive of therapeutic benefit with c10zapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of c10zapine (~ 900 mg/day) versus that of chlorpromazine (~ 1800 mg/day) in terms of physicians' and ward nurses' ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement.
Adverse Effects
Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of c1ozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (1\ %), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to c10zapine and necessitating its withdrawal (predominantly toxic delirium and sedation) oc-
725
Clozapine: A Review
curred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period. Agranulocytosis is the most serious adverse effect of clozapine, occurring in I to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown. Clozapine is distinguished from the traditional anti psychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy. Dosage and Administration
Clozapine may be administered orally or intramuscularly. The manufacturer recommends initiation of clozapine therapy with 25 to 75 mgjday administered in 2 or 3 divided doses, followed by titration in 25 to 50 mgjday increments to achieve a target dose of 300 to 450 mg/day after 2 weeks. Subsequent dosage increases of ~ 100 mgjday should be performed no more than twice weekly, to a maximum dose of 900 mg/day. After initial titration, the dose should be progressively reduced to the minimum level necessary to maintain clinical remission. In view of the continuing risk of agranulocytosis, weekly haematological surveillance is essential during the initial 18 weeks of clozapine administration; thereafter monthly monitoring is considered satisfactory. Clozapine is contraindicated in conjunction with drugs with the potential to depress bone marrow function/induce agranulocytosis, as well as in patients with severe CNS depression, myeloproliferative disorders or a history of drug-induced agranulocytosis.
Clozapine [8-chloro-ll-( 4-methyl-l-piperazinyl)-5H-dibenzo [1,4] diazepine] is a dibenzodiazepine derivative (fig. 1) with a pharmacological and therapeutic profile that distinguishes it from the classic anti psychotics (phenothiazines, butyrophenones, diphenylbutylpiperidines and thioxanthenes). In contrast to these latter groups, c10zapine exerts a relativel~ weak antidopaminergic action within the CNS and is only marginally effective in several animal behavioural tests considered to be specific for drugs with antipsychotic properties. Clinically, c10zapine is regarded as an atypical antipsychotic on account of its low propensity to produce extrapyramidal side effects and its lack of stimulatory effect on prolactin secretion. The drug has been used in the treatment of acute and chronic schizophrenia, mania, hypomania and other acute psychoses of diverse aetiology, as well as behavioural disorders characterised by aggressiveness, impulsiveness and excitability. This review focuses on the use of c10zapine in the treatment of schizophrenic disorders, defined for this purpose as schizophrenia, schizophreni-
form disorder and schizoaffective disorder (code 295 in the revised DSM-I1I classification).
1. Overview of Pharmacodynamic Properties It is generally acknowledged that the therapeutic effects of antipsychotic drugs are related to their actions on central dopaminergic mechanisms (Carlsson 1978; Creese et al. 1976; Seeman et al. 1976). The clinical potency of typical and atypical anti psychotics is closely correlated with their in vitro affinity for central dopamine D2-receptors (Peroutka & Snyder 1980; Richelson 1984), while therapeutic doses of these compounds produce a substantial in vivo blockade of central dopamine D2-receptors in patients with schizophrenia (Farde et al. 1988). In the case of c1ozapine, it appears unlikely that dopamine D2-receptor antagonism can fully account for the drug's antipsychotic efficacy. Although an effective antipsychotic, c10zapine differs from the typical antipsychotics in producing rela-
726
Drugs 40 (5) 1990
Clozapine
Fig. 1. C10zapine metabolites identified in the urine of schizophrenic and manic patients following oral administration of 300 to 800 mgjday (adapted from Stock et al. 1977).
tively weak antagonism at central dopamine 02receptors, more pronounced inhibition of dopamine 0 I-mediated activation of adenylate cyclase, and potent blockade of central serotonergic, adrenergic and cholinergic receptors (Altar et al. 1986; Souto et al. 1979). Moreover, c10zapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy and suppression of dopamine-induced stereotypy) considered to be predictive of antipsychotic activity. It has been suggested that the antipsychotic efficacy of c1ozapine might be related to central dopamine 01- or a combination of dopamine 01- and D2-receptor antagonism (Altar et al. 1988; Andersen & Braes-
trup 1986; Coward et al. 1989; Criswell et al. 1989), with serotonergic S2-receptor antagonism possibly playing a supplementary role (Meltzer 1989). The therapeutic effects of antipsychotic drugs are presumed to be mediated by mesolimbic and mesocortical dopaminergic pathways (Delini-Stula 1986; Stevens & Livermore 1978), while the neostriatum has been implicated in the extrapyramidal side effects associated with these drugs (Davis & Casper 1977; Hornykiewicz 1977). In view of the low incidence of extrapyramidal side effects with c1ozapine, it has been suggested that the atypical pharmacological profile of this drug might be attributable to a selective action on mesolimbic
Clozapine: A Review
727
dopaminergic mechanisms (Borison & Diamond 1983). 1.1 Effects on Central Neurotransmitter Systems In contrast to the classic anti psychotics, c1ozapine displays low in vitro affinity for striatal dopamine D2-receptors, and relatively greater affinity for striatal dopamine DI-, cortical/subcortical serotonin S2- and S3- and central al- and a2-adrenergic, histamine HI- and muscarinic receptors (Altar et al. 1986; Andersen & Braestrup 1986; Biirki 1986; Biirki et al. 1975b; Coward et al. 1989; Eichenberger 1984; Riehelson 1984; Watling et al. 1990; Wilmot & Szczepanik 1989) [tables I & II). In vitro binding is not necessarily predictive, however, of the functional effects of drug-receptor interactions in the intact organism. Clozapine exhibits relatively potent serotonergic S2- (Fink et al. 1984; Leysen et al. 1978), serotonergic S3- (Ashby et al. 1989; Watling et al. 1990), ai-adrenergic (Bartholini et al. 1973; Blumberg et al. 1976), histamine H 1- (Niemegeers & Janssen 1979) and muscarinic (Miller & Hiley 1976) antagonist activity (fig. 2), and appears to induce preferential blockade of dopamine DI- (versus dopamine 02-) receptors in vivo (Coward et al. 1989). In contrast to the classic anti psychotics, c10zapine shows greater potency in binding to the dopamine DI-receptor in vivo and inhibiting dopamine-stimulated adenylate cyclase activity than in competing for [3H]SCH 23390 (a
selective dopamine D I-antagonist) binding in vitro (Andersen & Braestrup 1986; Andersen et al. 1986). Positron emission tomography scan studies of relative dopamine DI- and D2-receptor occupancy in patients with schizophrenia undergoing antipsychotic therapy have indicated that, at clinically effective doses (300 to 600 mg/day), c10zapine produces comparable degrees of dopamine DI- and D2receptor blockade, and less dopamine D2-receptor blockade than do the classic anti psychotics (Farde et al. 1988, 1989), thereby lending support to the hypothesis that dopamine DI-antagonism may be of relevance to c1ozapine's antipsychotic action. Long term administration of c10zapine enhances striatal dopamine D 1- (but not dopamine D2-) receptor function in rats (Clark & White 1987; Jenner et al. 1985; Rupniak et al. 1985), and results in down-regulation of cortical serotonin S2-receptors (Lee & Tang 1984; Reynolds et al. 1983; Wilmot & Szczepanik 1989), further suggesting that an interaction with these 2 neurotransmitter systems may be a significant component of the drug's antipsychotic action. Pronounced serotonin S2- in relation to dopamine D2-receptor blockade has been postulated to be the central factor distinguishing atypical from typical anti psychotics (Meltzer et al. I 989c). It is noteworthy that serotonin S2-antagonist activity in antipsychotic drugs has been previously associated with efficacy against the negative symptoms of schizophrenia and a low propensity to induce extrapyramidal symptoms (Ceulemans et al. 1985).
Table I. Effects of clozapine . chlorpromazine and haloperidol on radioligand binding to preparations of human caudate nucleus and frontal cortex in vitro (after Richelson 1984) Radioligand
Receptor
Receptor affinity Ki (nmol/L) clozapine
[3Hlspiperone
Dopamine 02
chlorpromazine
haloperidol
180
19
4
12
[3Hlquinuclidinyl benzilate
Muscarinic
70
24000
[3Hldoxepin
Histamine HI
2.8
9
1900
[3Hlprazosin
Adrenergic al
9
2.6
[3Hlrauwolscine (a-yohimbine)
Adrenergic a 2
160
750
6.1 3800
728
Drugs 40 (5) 1990
Table II. Ellects of clozapine , chlorpromazine and haloperidol on dopamine 0,- and D2-receptor binding to rat striatum in vitro and on dopamine D,-receptor binding to mouse brain in vivo (after Andersen et al. 1986) Compound
Clozapine Chlorpromazine Haloperidol
Inhibition of [3HlSCH 23390 binding in vivo (EDso; mg/kg)'
Dopamine receptor allinity in vitro (Kj; nmol/L)b 0,
02
10.2
55
90
7.3
25
4.6
72.5
76
2.6
a The EDso value is the antipsychotic dose which reduces the specific in vivo binding of [3HlSCH 23390 by 50% in mouse brain. b Data from Andersen et al. (1985).
1.2 Differential Effects on Central Dopaminergic Systems Biochemical and neurophysiological studies in animals indicate that c10zapine may act preferentially on mesolimbic rather than neostriatal dopaminergic neurons. Clozapine has been reported to be more effective in increasing dopamine turnover and release in the nucleus accumbens or olfactory tubercle than in the neostriatum (Anden & Stock 1973; Bartholini 1976; Bowers & Rozitis 1974; Stawarz et al. 1975; Westerink & Korf 1976; Westerink et al. 1977; Zivkovic et al. 1975), although other studies have failed to confirm this selective action (Bartholini et al. 1975; Bowers & Rozitis 1976; Imperato & Angelucci 1988; Westerink & Korf 1975; Wilk & Glick 1976). On acute administration, c10zapine selectively enhanced neuronal activity in the mesolimbic system (Hand et al. 1987; White & Wang 1983) and increased dopamine release in the nucleus accumbens but not in the neostriatum (Huff & Adams 1980; Lane & Blaha 1986). In contrast, on chronic administration c10zapine selectively depressed neuronal activity in the mesolimbic system (Chiodo & Bunney 1983; White & Wang 1983) and reduced dopamine release in the nucleus accumbens (Blaha & Lane 1987; Lane et al. 1988). Dopamine synthesis and metabolism, however, were
nonselectively increased in both the neostriatum and mesolimbic system during short term c1ozapine administration (Walters & Roth 1976; Wilk et al. 1975). A possible explanation for the apparently selective action of c10zapine on the mesolimbic system might be a concomitant interaction with other neurotransmitter systems compensating for dopaminergic blockade in the neostriatum. Antagonism at cholinergic and/or ai-adrenergic receptors has been suggested to account for the apparently selective action of c10zapine on mesolimbic dopaminergic neurons, and the consequent low incidence of extrapyramidal side effects (see section 4.2) [Chiodo & Bunney 1983; Lane et al. 1988; Miller & Hiley 1974; Snyder et al. 1974]. The amygdala, which receives dopaminergic input from the substantia nigra and ventral tegmentum, may be an additional site of action of c10zapine. Amygdaloid neurons are excited by short (Rebec et al. 1981 , 1983) and long term (Anderson & Rebec 1986; Rebec & Anderson 1986) c10zapine administration, but are generally unresponsive to haloperidol and other standard anti psychotics. This differential effect is not observed in other forebrain
1---1"'100 I"'r--1"' 10 100 10
0.1
.2 ~
8'
...J
0.1 H
S
M
0.01
NA
0,01 Haloperido!
ClozaChlorpromazine pine
Fig. 2. Pharmacological profiles of action ofclozapine. chlorpromazine and haloperidol in relation to their antidopaminergic effects. The in vivo antagonistic potencies of each compound at adrenergic (NA), serotonergic (S). muscarinic (M) and histamine (H) receptors are expressed relative to its antagonistic potency at dopaminergic (DA) receptors (arbitrarily chosen as unity) [adapted from Delini-Stula 1986).
729
Clozapine: A Review
sites that receive dopaminergic input, including the neostriatum and nucleus accumbens, where clozapine and haloperidol display comparable effects on neuronal activity (Rebec et al. 1979, 1980). 1.3 Behavioural Effects in Animals Results from a series of animal behaviour models routinely used to screen for antipsychotic activity suggest that the neostriatum is relatively unresponsive to clozapine. In rodents, clozapine induces little or no catalepsy (Bartholini et al. 1972; Biirki et al. 1975a; De Maio 1972; Honma & Fukushima 1978), catalepsy being a characteristic response to neostriatal dopamine receptor blockade (Carlsson 1978). Amphetamine-induced locomotion, which is apparently mediated by enhanced dopaminergic neurotransmission in the nucleus accumbens (Kelly & Iversen 1976; Pijnenburg et al. 1976), is inhibited by acute administration of clozapine, whereas amphetamine-induced stereotypy (gnawing, grooming and sniffing), a response dependent on the integrity of the dopaminergic input to the neostriatum (Groves & Rebec 1976), is unaffected by the drug (Iversen & Koob 1977). Similarly, clozapine inhibits apomorphine-induced locomotion, but does not interfere with apomorphineinduced stereotypy (Ljungberg & Ungerstedt 1978). Hyperactivity elicited by direct injection of dopamine into the mesolimbic nuclei is blocked by clozapine at doses an order of magnitude lower than those required to block behaviours elicited by direct striatal dopamine injections (Costall & Naylor 1976). Chronic clozapine administration supersensitises those behaviours mediated via mesolimbic dopaminergic pathways (i.e. dopamine-induced locomotion), but not those mediated via neostriatal systems (i.e. dopamine-induced stereotypy) [Halperin et al. 1989). Drug-induced suppression of conditioned avoidance behaviour, which is considered predictive of antipsychotic activity (Kuribara & Tadokoro 1981; Niemegeers et al. 1969), has been demonstrated during acute clozapine administration in the rat (Biirki et al. 1975a; Davidson & Weidley 1976; Iorio et al. 1983; Sanger 1985). However, the
suppression of avoidance responding was manifest with relatively high (sedative) doses of clozapine and, in contrast to haloperidol, was associated with the rapid development of tolerance on repeat administration (Sanger 1985), thereby suggesting that this effect of clozapine is not specifically related to its antipsychotic action. In its effects on schedule-controlled behaviours (those reinforced by food or electrical self-stimulation), clozapine more closely resembled anxiolytics such as benzodiazepines than the classic anti psychotics (Atrens et al. 1976; Canon & Lippa 1977; Spealman et al. 1983; Wenger 1979). As an antipsychotic, clozapine is atypical in producing no oral dyskinesia in the rat on long term administration (Johansson et al. 1986; See & Ellison 1990). Moreover, in contrast to haloperidol, clozapine fails to elicit an acute dyskinetic syndrome in monkeys primed by long term haloperidol or fluphenazine pretreatment (Gunne & Barany 1979; Kovacic et al. 1986; Liebman & Neale 1980) or to modify tardive dyskinesia-like symptoms arising after antipsychotic withdrawal (Gunne & Barany 1979; Kovacic et al. 1986). 1.4 Neuroendocrinological Effects In the rat, acute administration of clozapine was associated with a transient rise in serum prolactin, corticotrophin (adrenocorticotrophic hormone) and corticosterone levels (Biirki et al. 1975a; Gudelsky et al. 1987b; Iorio et al. 1983) and an increase in the activity of tuberoinfundibular dopaminergic neurons (Gudelsky et al. 1987a), which have previously been shown to exert an inhibitory influence on prolactin release from the pituitary (Gudelsky 1981). In contrast to the prolonged stimulation of prolactin secretion produced by classic antipsychotics (Meltzer & Fang 1976), clozapine has minimal effects on serum prolactin levels in humans, despite its ability to block pituitary dopamine receptors (Kane et al. 1981; Meltzer 1989; Meltzer et al. 1979). It has been suggested that the failure of clozapine to stimulate prolactin secretion in humans may be the result of a clozapine-induced increase in tuberoinfundibular dopamine re-
730
Drugs 40 (5) 1990
-
(')
c:i
~
.~
"S
o
U
~ 3o
'"
If)
.r::
:2
HP
BPRS, CGI
NS
ClZ == PPZ
ClZ> lMP
ClZ == HP
BPRS
AMP
ClZ > HP BPRS; SGE
ClZ "CPZ
ClZ;;' CPZ
BPRS
ClZ 200-300 CPZ 200-600
6
ClZ == CPZ ClZ == CPZ
BPRS; GCS
6
ClZ 50-300 CPZ 75-600
ClZ " PPZ
ClZ < HP
ClZ " HP
ClZ == CPZ
ClZ > CPZ
BPRS
6
ClZ " CPZ
ClZ "CPZ
ClZ> CPZ
BPRS; SGE
ClZ 200-100(Jd CPZ 75-800d
7
CLZ 75-450 CPZ 150-900
ClZ == CPZ
ClZ== CPZ
ClZ;;' CPZ
extrapyramidal symptoms
6
6
ClZ 160-340 CPZ 130-410
Results overall efficacyb
BPRS; NOSIE
Rating scale
CLZ 600C CPZ 600C
6
Duration of treatment (weeks)
ClZ 150-300 CPZ 150-300
Daily dose (mg)
a Number of patients evaluated on completion of the study. b Overall therapeutic efficacy is assessed in terms of drug effect on individual and grouped parameters of psychiatric and social function. c Mean dose. d Mean clozapine and chlorpromazine doses 277 and 283 mg/day, respectively. Abbreviations and symbols: r = randomised; sb = single-blind; db = double-blind; co = crossover; p= parallel group trial; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression Scale; NOSIE = Nurses' Observation Scale for Inpatient Evaluation; GCS = Global Clinical Scale; SGE = Subjective Global Evaluation; AMP = Arbeitsgemeinschaft fUr Methodik und Dokumentation in der Psychiatrie; NS = not stated; == = similar effect; " tendency towards greater effect; > = statistically significant greater effect (p < 0.05); " = tendency towards a lower effect; < = statistically significant lower effect (p < 0.05).
Perphenazine (PPZ) Rodova et al. (1973)
12 17
12 12
SchOneil & Klieser (1988)
levomepromazine (lMP) Angst et al. (1971)
47 41
Itoh et al. (1977)
20
16 19
Guirguis et al. (1977)
Haloperidol (HP) Gerlach et al. (1974)
20 21
22 14
No. of patients·
Ekblom & Haggstrom (1974)
Chlorpromazine (CPZ) Chiu et al. (1976)
Reference
Table IV. Some single· and double-blind comparative studies of clozapine (ClZ) and other anti psychotics in the treatment of patients with schizophrenia
......
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oa
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.j:>.
Clozapine: A Review
clozapine than with chlorpromazine, commenced later, and were of shorter duration (Guirguis et al. 1977).
3.3.2 Haloperidol Short term (6 to 12 weeks) trials in patients with schizophrenia have indicated that clozapine 75 to 800 mg/day has either equivalent (Itoh et al. 1977) or significantly superior (Gerlach et al. 1974; SchOnell & Klieser 1988) overall therapeutic efficacy to haloperidol 3 to 40 mg/day. However, the two drugs differ markedly in their spectra of antipsychotic effects. While clozapine produced significant improvements in anxiety, tension, and the productive and negative schizophrenic symptoms, haloperidol was effective against the core symptoms of schizophrenia but lacked significant action against anxiety and tension (Gerlach et al. 1974). Clozapine proved to be significantly superior to haloperidol in its antidelusional, contact-promoting and anxiolytic/sedative effects (BPRS items: somatic concern, anxiety, guilt feelings, conceptual disorganisation, tension, mannerisms/posturing and hostility) [Gerlach et al. 1974; Itoh et al. 1977]. Although haloperidol was reported to be significantly superior to clozapine in improving motor retardation and blunted affect in the general schizophrenic population (ltoh et al. 1977), the converse was true in patients with predominantly negative schizophrenic symptoms, with clozapine producing a significantly greater improvement in emotional withdrawal, motor retardation and blunted affect than haloperidol (Paunovic et al. 1988). The therapeutic superiority of clozapine over haloperidol was particularly pronounced in severely disturbed patients with added symptoms of anxiety, tension and psychomotor agitation (Gerlach et al. 1974). The incidence of extrapyramidal side effects (notably hyperkinesia and akathisia) was significantly higher with haloperidol, while clozapine produced more marked hypersalivation (Itoh et al. 1977).
735
3.4 Use in Treatment-Resistant Schizophrenia A subgroup of patients with schizophrenia, constituting up to 20% of the total, is refractory to treatment with the classic antipsychotics and has a poor long term prognosis (Davis et al. 1980). Additionally, of the patients who initially respond to classic antipsychotic therapy, approximately 20 to 30% are liable to relapse despite maintenance therapy (Kane & Lieberman 1987). To this subgroup of drug-refractory patients must be added those who fail to tolerate the classic anti psychotics at clinically effective doses because of the development of severe extrapyramidal side effects, and the estimated 15% of patients who develop tardive dyskinesia on long term therapy (Jeste & Wyatt 1981; Klawans et al. 1980). In this section, clinical experience with clozapine is described in these various patient subgroups which collectively constitute a distinct category of 'treatment-resistant schizophrenia' .
3.4.1 Noncomparative Studies Several retrospective and prospective noncomparative studies have demonstrated that a substantial proportion of patients with chronic treatmentresistant schizophrenia show significant clinical improvement during clozapine therapy. Despite methodological limitations, results from short and long term (1 month to 13 years) retrospective studies consistently indicate that approximately 30 to 50% of patients with treatment-resistant schizophrenia show a markedly better improvement on clozapine than on previous standard antipsychotic therapy (Kuha & Miettinen 1986; Leppig et al. 1989; Lindstrom 1988; Naber et al. 1989; Povlsen et al. 1985). In these patients, positive schizophrenic symptoms, particularly hallucinations, delusions, unusual thought content, psychomotor hyperactivity and aggression, appeared to be most markedly reduced by clozapine (Kuha & Miettinen 1986; Leppig et al. 1989; Naber et al. 1989), although negative schizophrenic symptoms of mutism, blunted affect and anergia were also favourably influenced, most notably in the subgroups with hebephrenia and chronic residual schizophrenia
736
(Naber et al. 1989). Clozapine also had a beneficial effect on the level of social adaptation in patients with chronic treatment-resistant schizophrenia: of 62 in this category who were maintained on clozapine for 2 years, 39% were in employment during this period compared with only 3% in the year preceding initiation of clozapine therapy (Lindstrom 1988). Characteristically, clozapine produced a pronounced alleviation of positive schizophrenic symptoms and an improvement in the quality of remission during the initial 6 months of therapy, while its effects on negative schizophrenic symptoms became increasingly evident with continued therapy. Over the following 6-month to 3.5-year treatment period, positive and negative symptoms improved steadily and significantly, while the improvement in work capacity attained significance after 2.5 years. Consolidation of the improvement in the quality of remission during this period was attributable to the parallel improvements in negative symptoms and work capacity and a reduction in the frequency of relapses (Panteleeva et al. 1978). Prospective studies of the clinical efficacy of clozapine in chronic treatment-resistant schizophrenia have demonstrated significant improvements (> 20% decrease in total BPRS score from baseline) in approximately 40 to 60% of patients when assessed after 1.5 to 6 months' therapy; these were subsequently maintained during long term (~ 4 years) follow-up treatment (Mattes 1989; Meltzer et al. 1989a,b; Owen et al. 1989; Small et al. 1987). Moreover, the improvement in psychopathology resulting from clozapine therapy was associated with an improvement in social function, as assessed in terms of the Quality of Life and Global Assessment ratings, in the outpatient setting (Meltzer et al. 1989a,b) and a marked reduction in the need for rehospitalisation (Meltzer et al. 1989a). Analysis of the responses of the various patient subgroups constituting treatment-resistant schizophrenia indicated that patients intolerant of classic antipsychotics and showing tardive dyskinesia/extrapyramidal side effects responded significantly
Drugs 40 (5) 1990
better to clozapine therapy (~ 3 months duration), as assessed by total BPRS rating, than those refractory to previous antipsychotic therapy, while the outcome in patients with a history of antipsychotic-induced akathisia was marginally superior to that in those without a history ofakathisia (Owen et al. 1989). The same study demonstrated a marked symptomatic improvement after 3 or more months of clozapine therapy in 5 of 11 patients (45%) with moderate-to-severe tardive dyskinesia induced by previous antipsychotic therapy. In accordance with the results of retrospective studies, the greatest improvement in psychopathology (total BPRS score) occurred during the initial 6 weeks of clozapine therapy, although only 45% of drug responders were identified during this period (Meltzer et al. 1989b); after 3 and 12 months' therapy 74% and 100%, respectively, of drug responders were identified (Meltzer et al. 1989b). This would suggest that a 6- to 12-month treatment period may be appropriate before deciding to discontinue clozapine because of insufficient response. While clinical responsiveness to clozapine in treatment-resistant schizophrenia is reportedly unrelated to factors of age, sex, duration of illness, hospitalisation and presence or history of tardive dyskinesia (Owen et al. 1989), the influence of disease severity is unclear. A favourable clinical response to prolonged (~ 6 weeks) clozapine therapy has variously been associated with less severe underlying psychopathology, as rated by BPRS and Composite Schizophrenia Syndrome scores (Small et al. 1987) and with more severe psychopathology, as rated by total BPRS scores and BPRS factor scores for Paranoid Disturbance and Thinking Disturbance (Meltzer et al. 1989b). 3.4.2 Comparisons with Other Antipsychotics
Several recent short term (6 to 8 weeks) doubleblind studies have confirmed the antipsychotic efficacy of clozapine and have provided evidence of its superiority over chlorpromazine in well-defined groups of patients with treatment-resistant schizophrenia (Borison et al. 1988; Claghorn et al. 1987; Conley et al. 1988; Herrera et al. 1988; Kane et al. 1988) [table V]. A noteworthy feature of these stud-
TD or EPS induced on prior antipsychotic therapy
63 c 61 c
12 12
8 8
126c 139c
Claghorn et al. (1987)
Conley et al. (1988)
Herrera et al. (1988)
Kane et al. (1988)d
CLZ "" 900 CPZ"" 1800
Daily dose (mg)
CLZ 900 CPZ 1800
CLZ "" 900 CPZ "" 1800 + BTM "" 6
r,p,mc,pb CLZ "" 900 CPZ"" 1800 +BTM",,6
p,pb
r,p,pb
r,p,mc,pb CLZ 150-900 CPZ 300-1800
r,p,pb
Study design
6
6
6
8
6
BPRS; CGI; NOSIE; AIMS; SANRS
BPRS; AIMS; SANRS
BPRS; CGI; NOSIE; AIMS; SANRS
BPRS; CGI; NOSIE; AIMS; SANRS
BPRS
Duration Rating of scale treatment (weeks)
CLZ > CPZ
CLZ ,. CPZ
CLZ > CPZ
CLZ > CPZ
CLZ> CPZ
overall efficacyb
Results
CLZ
== CPZ CPZ> CLZ
NS
CLZ
CPZ ,. CLZ
CLZ
NS
== CPZ
== CPZ
tardive dyskinesia
CPZ,. CLZ
extrapyramidal symptoms
==
a Number of patients evaluated on completion of the study, unless otherwise stated, b Overall therapeutic efficacy is assessed in terms of drug effect on individual and grouped parameters of psychiatric and social function. c Number of patients included in the endpoint analysis on completion of a minimum of 1 week's therapy, d Multicentre study incorporating those patients referred to in the single centre studies of Borison et ai., Conley et al. and Herrera et al. Abbreviations and symbols: BTM = benztropine mesylate; HP = haloperidol; TD = tardive dyskinesia; EPS = extrapyramidal symptoms; NS = not stated; r = randomised; p = parallel group trial; mc = multicentre trial; pb = placebo washout period; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression Scale; NOSIE = Nurses' Observation Scale for Inpatient evaluation; SANRS = Simpson-Angus Neurological Rating scale; AIMS = Abnormal Involuntary Movement Scale; = similar effect; ,. tendency towards greater effect; > = statistically significant greater effect (p < 0.05); "" = tendency towards a lower effect; < = statistically significant lower effect (p < 0.05),
Refractory to previous antipsychotic therapy; proven refractoriness to HP (60 mg/day)
Proven refractoriness to HP (60 mg/day)
Refractory to previous antipsychotic therapy; proven refractoriness to HP (60 mg/day; CGI ,. 4; BPRS ,. 36)
Refractory to previous antipsychotic therapy; proven refractoriness to HP (,. 60 mg/day)
14 13
No. of Therapeutic status patients a
Borison et al. (1988)
Reference
Table V. Some double-blind comparative studies of clozapine (CLZ) and chlorpromazine (CPZ) in patients with treatment-resistant schizophrenia
---I
---I
,.:
(ii'
