European Neuropsychopharmacology, 1 (1991) 541 548 © 1991 Elsevier Science Publishers B.V. / All rights reserved / 0924-977X/91/$3.50
541
ENP 00040
Zuclopenthixol, a combined dopamine D1/D2 antagonist, versus haloperidol, a dopamine D2 antagonist, in tardive dyskinesia H e n r i k L u b l i n l, Jes G e r l a c h 1, U l f H a g e r t 2, Birgit M e i d a h l l, Cecilia M o l b j e r g 3, V a g n P e d e r s e n 3, Claus R e n d t o r f f 1 a n d Erkki T o l v a n e n 2 1Sct. Hans Hospital, Department P, Roskilde (Denmark), 2Nickby Sjukhus, Nickby (Finland), and 3H. Lundbeck A/S, Copenhagen (Denmark) (Received I l April, 1991) (Revised, received 16 September, 1991) (Accepted 24 September, 1991)
Key words." Tardive dyskinesia; Parkinsonism; Dopamine D~ and D2 receptors; Dopamine supersensitivity Summary Animal data suggest that a D1 antagonistic component in neuroleptic drugs counteracts development of dopamine supersensitivity and of tolerance to cataleptic effect. This has led to the hypothesis that neuroleptics with D1 antagonistic activity should cause a better suppression of tardive dyskinesia (TD) and less rebound aggravation after withdrawal than pure D2 antagonists. In this study the effect of zuclopenthixol (mixed D1/D2 antagonist) and haloperidol (D 2 antagonist) was evaluated in chronic psychotic patients with TD. Fifteen patients completed a randomized crossover study with blind evaluation of TD and parkinsonism. The test medications, haloperidol and zuclopenthixol, caused a significant suppression of TD and a significant increase of parkinsonism. No significant differences between haloperidol and zuclopenthixol were observed. No TD aggravation was seen. The lack of differences between the mixed D1/D2 antagonist and a D2 antagonist suggest that tolerance and DA supersensitivity play no or a minor role for development of TD.
Introduction Tardive dyskinesia (TD) is a serious side effect of neuroleptic treatment (Jeste and Wyatt, 1982; Casey et al., 1985; Gerlach and Casey, 1988). In spite of intensive research, the pathophysiology of TD is still not clarified. According to the traditional hypothesis, TD is related to supersensitivity of the dopaminergic system of the brain following long-term neuroleptic treatment (Klawans, 1973; Baldessarini et al., 1980; Tarsy, 1983). Correspondence to: Henrik Lublin, MD, University Hospital, Rigshospitalet, Psychiatric Department, DK-2100 Copenhagen O, Denmark. Phone: 45 35453545/6161.
Other potential pathophysiological mechanisms include a blockade of a subset of dopamine (DA) receptors (Scheel-Krfiger and Arnt, 1985; Gerlach and Casey, 1988), a disturbed balance between DA D1 and D2 receptor functions with D~ dominance (Gerlach and Casey, 1988; Lublin and Gerlach, 1988), a dysfunction of the GABA system (Gunne et al., 1984; Scheel-Krfiger and Arnt, 1985), and a noradrenergic hyperfunction (Jeste et al., 1986). In rodents, it has been found that compared to selective D2 antagonists neuroleptic drugs with a Dl antagonistic component produce little or no tolerance to the cataleptic effect and less DA supersensitivity after withdrawal (Christensen et al., 1985a). Thus DI antagonists as well as D2
542 antagonists inhibit DA agonist-induced stereotyped gnawing, but the D2 antagonist haloperidol induces marked tolerance and DA supersensitivity, while the mixed DI/D2 antagonist zuclopenthixol and the selective DI antagonist SCH 23390 only cause slight tolerance and weak or no supersensitivity. Even a low dose of a Dl antagonist is sufficient to reverse the tolerance and supersensitivity induced by the D2 antagonist haloperidol (Christensen et al., 1985a,b). If these mechanisms (tolerance and DA supersensitivity) play a role in TD, it might be expected that TD is more effectively suppressed during treatment and is induced or aggravated to less extent following withdrawal of neuroleptic drugs with both DA D1 and D2 receptor blocking qualities than selective DA D2 receptor blocking neuroleptic drugs (see also Glenthoj et al., 1989). The aim of this study was to evaluate the effect of zuclopenthixol (ZPT) (a combined DA Dr/D2 receptor antagonist) and haloperidol (HAL) (a selective D2 receptor antagonist) in TD, with special focus on the potential suppression of TD and concomitant induction of parkinsonism during test medication, and the aggravation of TD qfter test medication (i.e., the potential TD-inducing effect).
included in the study, provided they satisfied the following criteria: informed consent from patient or relatives; male or female above 18 years; duration of neuroleptic treatment at least 2 years; a total TD score of at least 3 on the rating scale used (see later) during previous neuroleptic treatment; duration of TD at least 6 months. Excluded were patients with severe somatic or neurological diseases, alcohol or drug abuse, pregnancy, outpatients and patients with severe psychotic symptoms unable to co-operate in the study. Design and medication
The study was planned as an randomized crossover trial (in which each patient in the two test phases would receive treatment with HAL and ZPT, respectively) with wash-out periods and blind evaluation or TD and parkinsonism (PARK) by means of video recordings. The trial course was divided into five phases (Fig. 1). In the pretrial phase, the patients were titrated to the lowest possible dose of the basic neuroleptic medication (HAL), sufficient to keep the patients in an optimal mental condition. This dose of HAL (basic medication) was kept constant at least 4 weeks before the first test phase and during the rest of the study. The patients were then randomized to receive either H A L or ZPT in the first test phase. The group of patients that received HAL in the first test phase is called HAL-ZPT, the group that received ZPT is called ZPT-HAL. In the first test phase, the patients were given the test medication (HAL or
Material and methods Pa tien t se lec t ion
Psychotic psychiatric in-patients with TD were
HAL
HAL
RANDOMIZATION
l
"i
i
I
I I
! I
TREATMENT
ZPT
ZPT FIRST
I I TEST I PHASE I 2 3 I I
P R E T R I A L PHASE
-4 I
WEEKS
BPRS VIDEO RECORDING SIDE E F F E C T S EVALUATION
x
X
FIRST
I SECONDI
',TEST
4 I
WASH-OUT PHASE 5 7 I I
I PHASE I PHASE g 11 12 13 14 16 I I I I I I
X
X
SECOND
',
WASH-OUT 18 I
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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X
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Fig. 1. Flow chart scheme of the study. The course of the study with randomization is shown above. Solid line: patients allocated to haloperidol in the first test phase (HAL-ZPT); broken line: patients allocated to zuclopenthixol in the first test phase (ZPT-HAL). The five phases of the study are indicated in the middle, while the time points of evaluation are shown below.
543 ZPT) for 3 weeks (in addition to the basic medication HAL). During the first 2 weeks the dose of the test medication was adjusted to suppress TD as much as possible, still keeping the other side effects at an acceptable level. During the last week of the test phase the dose was kept constant. In the first wash-out period, test medication was stopped for 6 weeks (with continued basic medication). In the second test phase, the patients had the alternative test medication for 3 weeks just as in the first test phase. In the second wash-out period, test medication again was stopped for 6 weeks. The duration of the whole study was 22-30 weeks, depending on the length of the pretrial phase. The basic medication (HAL) was administered as tablets (b.i.d.). Test medication was given as tablets (b.i.d.). A dose relationship of HAL/ZPT of 1:4 was used (based on the antipsychotic properties of the 2 drugs (Heikkil/i et al., 1981; Heikkil/i et al., 1991). The initial dose for HAL was 0.5 mg b.i.d. and for ZUC 2 mg b.i.d. At the days of evaluation and video recording (see below) a blood sample was taken (12 h after the last drug dose) for determination of drug concentration (high-performance liquid chromatography; Aaes-Jorgensen, 1980) to evaluate compliance and to find fast metabolizers. During the treatment benzodiazepines were allowed as antianxiety drugs. Other neuroleptic drugs, antidepressants and antiparkinsonian medication were not allowed.
Evaluation TD and PARK symptoms were recorded on videotapes at the time points shown in Fig. 1. All investigators were carefully instructed in performing these recordings according to a standardized examination procedure which included sitting, standing, walking, distraction by conversation and performing voluntary movements such as writing. All the videotapes were later randomly sequenced and blindly scored by two of the same three raters (HL, JG, CR; interrater reliabilities were between r=0.8462 and r=0.8804, P
541
ENP 00040
Zuclopenthixol, a combined dopamine D1/D2 antagonist, versus haloperidol, a dopamine D2 antagonist, in tardive dyskinesia H e n r i k L u b l i n l, Jes G e r l a c h 1, U l f H a g e r t 2, Birgit M e i d a h l l, Cecilia M o l b j e r g 3, V a g n P e d e r s e n 3, Claus R e n d t o r f f 1 a n d Erkki T o l v a n e n 2 1Sct. Hans Hospital, Department P, Roskilde (Denmark), 2Nickby Sjukhus, Nickby (Finland), and 3H. Lundbeck A/S, Copenhagen (Denmark) (Received I l April, 1991) (Revised, received 16 September, 1991) (Accepted 24 September, 1991)
Key words." Tardive dyskinesia; Parkinsonism; Dopamine D~ and D2 receptors; Dopamine supersensitivity Summary Animal data suggest that a D1 antagonistic component in neuroleptic drugs counteracts development of dopamine supersensitivity and of tolerance to cataleptic effect. This has led to the hypothesis that neuroleptics with D1 antagonistic activity should cause a better suppression of tardive dyskinesia (TD) and less rebound aggravation after withdrawal than pure D2 antagonists. In this study the effect of zuclopenthixol (mixed D1/D2 antagonist) and haloperidol (D 2 antagonist) was evaluated in chronic psychotic patients with TD. Fifteen patients completed a randomized crossover study with blind evaluation of TD and parkinsonism. The test medications, haloperidol and zuclopenthixol, caused a significant suppression of TD and a significant increase of parkinsonism. No significant differences between haloperidol and zuclopenthixol were observed. No TD aggravation was seen. The lack of differences between the mixed D1/D2 antagonist and a D2 antagonist suggest that tolerance and DA supersensitivity play no or a minor role for development of TD.
Introduction Tardive dyskinesia (TD) is a serious side effect of neuroleptic treatment (Jeste and Wyatt, 1982; Casey et al., 1985; Gerlach and Casey, 1988). In spite of intensive research, the pathophysiology of TD is still not clarified. According to the traditional hypothesis, TD is related to supersensitivity of the dopaminergic system of the brain following long-term neuroleptic treatment (Klawans, 1973; Baldessarini et al., 1980; Tarsy, 1983). Correspondence to: Henrik Lublin, MD, University Hospital, Rigshospitalet, Psychiatric Department, DK-2100 Copenhagen O, Denmark. Phone: 45 35453545/6161.
Other potential pathophysiological mechanisms include a blockade of a subset of dopamine (DA) receptors (Scheel-Krfiger and Arnt, 1985; Gerlach and Casey, 1988), a disturbed balance between DA D1 and D2 receptor functions with D~ dominance (Gerlach and Casey, 1988; Lublin and Gerlach, 1988), a dysfunction of the GABA system (Gunne et al., 1984; Scheel-Krfiger and Arnt, 1985), and a noradrenergic hyperfunction (Jeste et al., 1986). In rodents, it has been found that compared to selective D2 antagonists neuroleptic drugs with a Dl antagonistic component produce little or no tolerance to the cataleptic effect and less DA supersensitivity after withdrawal (Christensen et al., 1985a). Thus DI antagonists as well as D2
542 antagonists inhibit DA agonist-induced stereotyped gnawing, but the D2 antagonist haloperidol induces marked tolerance and DA supersensitivity, while the mixed DI/D2 antagonist zuclopenthixol and the selective DI antagonist SCH 23390 only cause slight tolerance and weak or no supersensitivity. Even a low dose of a Dl antagonist is sufficient to reverse the tolerance and supersensitivity induced by the D2 antagonist haloperidol (Christensen et al., 1985a,b). If these mechanisms (tolerance and DA supersensitivity) play a role in TD, it might be expected that TD is more effectively suppressed during treatment and is induced or aggravated to less extent following withdrawal of neuroleptic drugs with both DA D1 and D2 receptor blocking qualities than selective DA D2 receptor blocking neuroleptic drugs (see also Glenthoj et al., 1989). The aim of this study was to evaluate the effect of zuclopenthixol (ZPT) (a combined DA Dr/D2 receptor antagonist) and haloperidol (HAL) (a selective D2 receptor antagonist) in TD, with special focus on the potential suppression of TD and concomitant induction of parkinsonism during test medication, and the aggravation of TD qfter test medication (i.e., the potential TD-inducing effect).
included in the study, provided they satisfied the following criteria: informed consent from patient or relatives; male or female above 18 years; duration of neuroleptic treatment at least 2 years; a total TD score of at least 3 on the rating scale used (see later) during previous neuroleptic treatment; duration of TD at least 6 months. Excluded were patients with severe somatic or neurological diseases, alcohol or drug abuse, pregnancy, outpatients and patients with severe psychotic symptoms unable to co-operate in the study. Design and medication
The study was planned as an randomized crossover trial (in which each patient in the two test phases would receive treatment with HAL and ZPT, respectively) with wash-out periods and blind evaluation or TD and parkinsonism (PARK) by means of video recordings. The trial course was divided into five phases (Fig. 1). In the pretrial phase, the patients were titrated to the lowest possible dose of the basic neuroleptic medication (HAL), sufficient to keep the patients in an optimal mental condition. This dose of HAL (basic medication) was kept constant at least 4 weeks before the first test phase and during the rest of the study. The patients were then randomized to receive either H A L or ZPT in the first test phase. The group of patients that received HAL in the first test phase is called HAL-ZPT, the group that received ZPT is called ZPT-HAL. In the first test phase, the patients were given the test medication (HAL or
Material and methods Pa tien t se lec t ion
Psychotic psychiatric in-patients with TD were
HAL
HAL
RANDOMIZATION
l
"i
i
I
I I
! I
TREATMENT
ZPT
ZPT FIRST
I I TEST I PHASE I 2 3 I I
P R E T R I A L PHASE
-4 I
WEEKS
BPRS VIDEO RECORDING SIDE E F F E C T S EVALUATION
x
X
FIRST
I SECONDI
',TEST
4 I
WASH-OUT PHASE 5 7 I I
I PHASE I PHASE g 11 12 13 14 16 I I I I I I
X
X
SECOND
',
WASH-OUT 18 I
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fig. 1. Flow chart scheme of the study. The course of the study with randomization is shown above. Solid line: patients allocated to haloperidol in the first test phase (HAL-ZPT); broken line: patients allocated to zuclopenthixol in the first test phase (ZPT-HAL). The five phases of the study are indicated in the middle, while the time points of evaluation are shown below.
543 ZPT) for 3 weeks (in addition to the basic medication HAL). During the first 2 weeks the dose of the test medication was adjusted to suppress TD as much as possible, still keeping the other side effects at an acceptable level. During the last week of the test phase the dose was kept constant. In the first wash-out period, test medication was stopped for 6 weeks (with continued basic medication). In the second test phase, the patients had the alternative test medication for 3 weeks just as in the first test phase. In the second wash-out period, test medication again was stopped for 6 weeks. The duration of the whole study was 22-30 weeks, depending on the length of the pretrial phase. The basic medication (HAL) was administered as tablets (b.i.d.). Test medication was given as tablets (b.i.d.). A dose relationship of HAL/ZPT of 1:4 was used (based on the antipsychotic properties of the 2 drugs (Heikkil/i et al., 1981; Heikkil/i et al., 1991). The initial dose for HAL was 0.5 mg b.i.d. and for ZUC 2 mg b.i.d. At the days of evaluation and video recording (see below) a blood sample was taken (12 h after the last drug dose) for determination of drug concentration (high-performance liquid chromatography; Aaes-Jorgensen, 1980) to evaluate compliance and to find fast metabolizers. During the treatment benzodiazepines were allowed as antianxiety drugs. Other neuroleptic drugs, antidepressants and antiparkinsonian medication were not allowed.
Evaluation TD and PARK symptoms were recorded on videotapes at the time points shown in Fig. 1. All investigators were carefully instructed in performing these recordings according to a standardized examination procedure which included sitting, standing, walking, distraction by conversation and performing voluntary movements such as writing. All the videotapes were later randomly sequenced and blindly scored by two of the same three raters (HL, JG, CR; interrater reliabilities were between r=0.8462 and r=0.8804, P
